Autophagy and ALS: mechanistic insights and therapeutic implications
Open accessAbstract
: ALS: amyotrophic lateral sclerosis; Atg: autophagy-related; CHMP2B: charged multivesicular body protein 2B; DPR: dipeptide repeat; FTD: frontotemporal dementia; iPSC: induced pluripotent stem cell; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; PINK1: PTEN induced kinase 1; RNP: ribonuclear protein; sALS: sporadic ALS; SPHK1: sphingosine kinase 1; TARDBP/TDP-43: TAR DNA binding protein; TBK1: TANK-binding kinase 1; TFEB: transcription factor EB; ULK: unc-51 like autophagy activating kinase; UPR: unfolded protein response; UPS: ubiquitin-proteasome system; VCP: valosin containing protein.
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TL;DR
This review synthesizes mechanistic links between autophagy dysfunction and ALS, focusing on ALS-associated mutations in autophagy-related genes and cell type-specific regulation of autophagy. It argues that effective autophagy-based therapies will require targeting the pathway in specific cell types rather than indiscriminate induction.
Key findings
- ALS-related mutations affect multiple autophagy stages and factors, including SQSTM1, C9orf72, TBK1, UBQLN2, FUS, VCP, OPTN, and CHMP2B; these mutations impair selective autophagy, mitophagy, autophagosome maturation, or autophagic flux.
- Reported mutation frequencies include C9orf72 expansion in 23–47% of familial ALS/FTD and 4–21% of sporadic disease; TBK1 mutations in ~1% of familial or sporadic ALS; OPTN mutations in ~3% of familial and ~1% of sporadic ALS; VCP mutations in ~1–2% of familial ALS; and SQSTM1 mutations in ~1–3.5% of ALS-FTD cases.
- Autophagy regulation differs by cell type: neurons are insensitive or only mildly responsive to starvation and MTOR inhibition, whereas astrocytes, oligodendrocytes, Schwann cells, and skeletal muscle respond to these stimuli; neuronal autophagy can be induced by MTOR/AKT-independent compounds such as 10-NCP.
- Therapeutic implications are mixed: rapamycin can worsen disease in SOD1G93A ALS mice, lithium showed no clinical benefit in five ALS trials, and a phase II rapamycin trial in ALS began in 2018 with results not yet published.
Methods
- Narrative review of the autophagy pathway, ALS-associated autophagy-related mutations, disease models, and cell type-specific autophagy regulation.
- No primary experimental design, sample, or statistical analysis is reported; the paper synthesizes published cell, animal, iPSC, and human data.
- Main analysis is conceptual integration of mechanistic findings to identify therapeutic targets and remaining questions.
Limitations
- The authors state that mechanistic details of autophagy’s neuroprotective role, neuronal resistance to autophagy induction, neuron-specific effects of autophagy-impairing mutations, and non-cell autonomous contributions to ALS pathogenesis remain incompletely defined.
- The authors note that cell type-specific autophagy regulation is insufficiently explored, that cell and animal models may not faithfully reproduce human autophagy regulation, and that LC3-II accumulation cannot distinguish true autophagy induction from late-stage inhibition.
- Evident from the text: this is a review without a systematic search strategy or primary data, and it relies on model systems that may not fully translate to human disease.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
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- Premisecitation
Mutations detected in the SQSTM1 promoter region are associated with reduced SQSTM1 protein levels in familial ALS-FTD.
“Additionally, mutations detected in the SQSTM1 promoter region are associated with reduced SQSTM1 protein levels in familial ALS-FTD [132,133].”
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In C9orf72-related ALS and FTD, SQSTM1 accumulates together with ubiquitin in neurons and glia as well as muscle fibers.
“In the most commonly inherited form of ALS and FTD due to mutations in the C9orf72 gene (described below), SQSTM1 accumulates together with ubiquitin in neurons and glia [119–121] as well as muscle fibers [122].”
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Individuals with disease-associated C9orf72 mutations display a significantly greater burden of SQSTM1-positive glial inclusions than those with sporadic ALS.
“In fact, individuals with disease-associated C9orf72 mutations display a significantly greater burden of SQSTM1-positive glial inclusions than those with sporadic ALS [82].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [82] Lorente Pons A, 2020, J Pathol source
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- Premisecitation
The C9orf72 hexanucleotide repeat expansion is the most common genetic cause of inherited ALS and FTD, accounting for 23-47% of familial cases and 4-21% of sporadic disease.
“In 2011, the seminal discovery of disease-associated expansion mutations within the C9orf72 gene uncovered the most common genetic cause of inherited ALS and FTD, accounting for 23–47% of familial cases and 4–21% of sporadic disease.”
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Nearly every neurodegenerative disorder is marked by accumulation of misfolded proteins within or adjacent to affected neurons and glia.
“This notion is underscored by the fact that nearly every neurodegenerative disorder is marked by the accumulation of misfolded proteins within or adjacent to affected neurons and glia, in spite of heterogeneous clinical and pathological characteristics among these diseases [68,69].”
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- Premisecitation
SQSTM1 is a major component of neuronal and glial cytoplasmic inclusions in Alzheimer disease and Parkinson disease.
“SQSTM1 is a major component of neuronal and glial cytoplasmic inclusions that characterize many neurological disorders such as Alzheimer disease and Parkinson disease [114,115].”
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Selective autophagy uses receptor proteins such as SQSTM1/p62, NBR1, and AMBRA1 that contain an LIR and separate motifs for binding polyubiquitinated proteins, targeting ubiquitinated proteins to phagophores for degradation.
“Although autophagic cargo can be trapped passively within the autophagosome in nonselective autophagy, direct substrate recruitment to phagophores in selective autophagy is mediated by a series of receptor proteins (e.g., SQSTM1/p62 [sequestosome 1], NBR1, AMBRA1) that contain both an LC3-interacting region (LIR) and separate motifs for binding polyubiquitinated proteins [41].”
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- Interpretationcitation
Antibodies specific for each DPR stain SQSTM1-positive inclusions, suggesting that DPRs are targeted for clearance by the UPS and/or autophagy.
“Antibodies specific for each dipeptide repeat (DPR) also stain SQSTM1-positive inclusions, including the star-like inclusions unique to C9orf72-related disease, suggesting that DPRs are targeted for clearance by the UPS and/or autophagy [119,169–171] (Figure 1).”
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ALS-FTD due to C9orf72 mutations displays TARDBP pathology, consisting of granular neuronal cytoplasmic inclusions, diffuse neuronal cytoplasmic staining, and glial cytoplasmic inclusions rich in TARDBP.
“ALS-FTD due to C9orf72 mutations displays TARDBP pathology, consisting of granular neuronal cytoplasmic inclusions, diffuse neuronal cytoplasmic staining, and glial cytoplasmic inclusions rich in TARDBP [120].”
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- Premisecitation
Loss of endogenous murine C9orf72 results in glial activation, impaired autophagy and toxicity when combined with the C9orf72 expansion mutation.
“On the other hand, loss of endogenous murine C9orf72 results in glial activation, impaired autophagy and toxicity when combined with the C9orf72 expansion mutation [173].”
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- Premisecitation
The C9orf72-SMCR8-WDR41 complex acts as a guanine nucleotide exchange factor for RAB8A and RAB39B, regulating vesicle trafficking and autophagic flux.
“Separately, the C9orf72-SMCR8-WDR41 complex acts as a guanine nucleotide exchange factor for RAB8A and RAB39B, regulating vesicle trafficking and autophagic flux [148].”
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- Premisecitation
Through interactions with ULK1 and RAB1A, C9orf72 promotes autophagy initiation.
“Additionally, through its interactions with ULK1 and RAB1A, a GTP-binding protein involved in vesicular protein trafficking and MTOR regulation [151,152], C9orf72 promotes autophagy initiation [153].”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationcitation
Loss of C9orf72 function and consequent impairment in autophagy may enhance DPR accumulation in C9orf72 mutation carriers, acting synergistically to accentuate neurodegeneration.
“Furthermore, the loss of C9orf72 function and consequent impairment in autophagy may enhance DPR accumulation in C9orf72 mutation carriers, acting synergistically to accentuate neurodegeneration [154,172,173].”
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Through phosphorylation of the autophagy receptors OPTN, SQSTM1, and CALCOCO2/NDP52, TBK1 regulates macroautophagy, xenophagy and mitophagy.
“Through its phosphorylation of the autophagy receptors OPTN, SQSTM1, and CALCOCO2/NDP52 (calcium binding and coiled-coil domain 2) [58,59,194], TBK1 regulates several aspects of autophagy, including macroautophagy, xenophagy and mitophagy [59,90,148,194–196].”
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- Interpretationreasoning
The endogenously encoded C9orf72 repeat expansion mutation leads to toxicity by both gain and loss of function mechanisms.
“These results are consistent with those in animal models, suggesting that the endogenously encoded C9orf72 repeat expansion mutation leads to toxicity by both gain and loss of function mechanisms.”
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Overexpression of ALS-linked UBQLN2 mutants interrupts the interaction between UBQLN2 and ATG9-ATG16L1.
“Overexpression of ALS-linked UBQLN2 mutants interrupts the interaction between UBQLN2 and ATG9-ATG16L1 [225]”
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- Premisecitation
Most ALS-associated TBK1 mutations affect the kinase and the coiled-coiled domains, both of which are vital for TBK1 function.
“Consistent with this, most ALS-associated TBK1 mutations affect the kinase and the coiled-coiled domains, both of which are vital for TBK1 function [206].”
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- Premisecitation
Autophagy activation via PI3K, AKT or MTOR inhibition reverses stress granule accumulation caused by ALS-linked mutant FUS.
“autophagy activation via PI3K, AKT or MTOR inhibition reverses stress granule accumulation caused by ALS-linked mutant FUS [236]”
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- Premisecitation
Tbk1 deletion disrupts the migration of T-cells that may exert anti-inflammatory effects in ALS models.
“In keeping with this, Tbk1 deletion disrupts the migration of T-cells [216] that may exert anti-inflammatory effects in ALS models [192,217].”
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Rare UBQLN2 mutations are associated with familial forms of ALS and ALS-FTD.
“Rare UBQLN2 mutations are associated with familial forms of ALS and ALS-FTD [221–223]”
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Autophagy induction extends survival in a Drosophila model of FUS-ALS.
“autophagy induction extends survival in a Drosophila model of FUS-ALS [236].”
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- Premisecitation
UBQLN2 can act as an autophagy receptor by directly interacting with LC3 in autophagosomes.
“UBQLN2 can also act as an autophagy receptor by directly interacting with LC3 in autophagosomes [219,220].”
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FUS-positive inclusions are autophagy substrates.
“suggesting that FUS-positive inclusions are autophagy substrates [235].”
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TBK1 mutations occur more frequently in patients with combined ALS-FTD than in those with ALS alone.
“Supporting the link between ALS and FTD, TBK1 mutations have also been identified in FTD patients, and in fact occur more frequently in patients with combined ALS-FTD than in those with ALS alone [207–209].”
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UBQLN2 colocalizes with SQSTM1 and ubiquitin in neuronal aggregates characteristic of ALS and ALS-FTD.
“UBQLN2 colocalizes with SQSTM1 and ubiquitin in neuronal aggregates characteristic of both ALS and ALS-FTD [221,224].”
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In cultured neurons, mutant FUS impairs stress granule clearance.
“In cultured neurons, mutant FUS impairs stress granules clearance; this effect is exacerbated by genetic loss of ATG5, enhancing stress granule accumulation and, ultimately, leading to cell death [235].”
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TBK1 mutations are responsible for ~1% of patients with familial or otherwise sporadic ALS.
“Whole exome sequencing studies revealed that mutations in TBK1 are also responsible for ~1% of patients with familial or otherwise sporadic ALS [205,206].”
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Whether TBK1 acts on autophagy or innate immunity may partially depend on its associations with specific adaptor proteins such as NAP1L1, TANK and TBKBP1/SINTBAD that bind in a mutually exclusive manner.
“Whether TBK1 acts on autophagy or innate immunity may partially depend on its associations with specific adaptor proteins such as NAP1L1 (nucleosome assembly protein 1), TANK and TBKBP1/SINTBAD that bind in a mutually exclusive manner [58,200,201].”
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FUS may exert a direct influence on autophagy initiation and autophagosome elongation by maintaining expression of factors including RB1CC1 and ATG16L1.
“FUS may exert a direct influence on autophagy initiation and autophagosome elongation by maintaining expression of factors including RB1CC1 and ATG16L1, which are diminished after CRISPR-mediated knockout of Fus but restored with re-introduction of wild-type FUS in N2A cells [237].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [237] Arenas A, 2020, J Neurochem
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Mutations in VCP most commonly lead to the combined disorder of inclusion body myopathy, Paget disease of the bone, and FTD (IBMPFD).
“Mutations in VCP most commonly lead to the combined disorder of inclusion body myopathy, Paget disease of the bone, and FTD (IBMPFD) [240]”
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- Interpretationreasoning
Disrupted autophagy and proteostasis likely play a key role in the pathogenesis of sporadic ALS.
“Disrupted autophagy and proteostasis are not only apparent in experimental models of familial ALS, with defined genetic mutations impairing autophagy effectors or imparting proteotoxic stress, but also likely play a key role in the pathogenesis of sporadic ALS (sALS).”
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Few phenotypes were noted in chmp2b knockout animals.
“few phenotypes were noted in chmp2b knockout animals [271]”
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In humans with sALS, pathologic inclusions found in motor neurons are surrounded by LC3 and SQSTM1.
“In humans with sALS, pathologic inclusions found in motor neurons are surrounded by LC3 and SQSTM1 [273]”
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- Interpretationcitation
ALS-associated OPTN mutations may accentuate neuronal loss secondary to neuroinflammation.
“which may accentuate neuronal loss secondary to neuroinflammation [261].”
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- Premisecitation
CHMP2B mutations were subsequently identified in ALS patients with a lower motor neuron predominant syndrome.
“CHMP2B mutations were subsequently identified in ALS patients with a lower motor neuron predominant syndrome [266,267].”
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Mutant VCP iPSC-derived astrocytes were unable to sufficiently support motor neuron survival.
“mutant VCP iPSC-derived astrocytes were unable to sufficiently support motor neuron survival, indicating the presence of non-cell autonomous mechanisms of neurodegeneration in VCP-related diseases [252].”
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- Interpretationcitation
Failed or stalled clearance via autophagy occurs in sALS.
“suggesting failed or stalled clearance via autophagy.”
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ALS-associated OPTN mutations enhance microglial NFKB1 expression.
“ALS-associated OPTN mutations enhance microglial NFKB1 expression [260]”
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Enlarged and acidified autophagic vacuoles accumulate in cells expressing disease-associated VCP mutants.
“enlarged and acidified autophagic vacuoles accumulate in cells expressing disease-associated VCP mutants, suggesting a late-stage block in the fusion of lysosomes with autophagosomes [249].”
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- Premisecitation
CHMP2B is a subunit of the endosomal sorting complex required for transport-III (ESCRT-III).
“CHMP2B (charged multivesicular body protein 2B) is a subunit of the endosomal sorting complex required for transport-III (ESCRT-III) [262].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [262] Ghazi-Tabatabai S, 2009, Biochem Soc Trans source
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OPTN directly interacts with SQSTM1 to form an autophagy receptor complex that accelerates autophagy flux.
“OPTN also directly interacts with SQSTM1 to form an autophagy receptor complex that accelerates autophagy flux [257].”
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- Interpretationreasoning
Pathogenic CHMP2B mutations act predominantly through gain-of-function toxicity.
“suggesting predominantly gain of function toxicity in association with pathogenic CHMP2B mutations.”
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Histopathological analyses consistently show TARDBP, ubiquitin and SQSTM1-positive inclusions in VCP-related diseases.
“Histopathological analyses consistently illustrate TARDBP, ubiquitin and SQSTM1-positive inclusions in VCP-related diseases [244–247].”
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Disease-associated CHMP2B mutations disrupt autophagy.
“suggesting that disease-associated CHMP2B mutations disrupt autophagy.”
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- Interpretationcitation
Disease-associated VCP mutants cause a late-stage block in the fusion of lysosomes with autophagosomes.
“suggesting a late-stage block in the fusion of lysosomes with autophagosomes [249].”
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Biochemical and histopathologic examination of frontotemporal cortex and spinal cord in sALS patients reveals that ubiquitin-positive inclusions contain TARDBP.
“biochemical and histopathologic examination of frontotemporal cortex and spinal cord in sALS patients reveals that ubiquitin-positive inclusions contain TARDBP [274,275]”
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CHMP2B mutations were initially associated with rare cases of chromosome 3-linked familial FTD.
“CHMP2B mutations were initially associated with rare cases of chromosome 3-linked familial FTD [264,265]”
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Non-cell autonomous mechanisms of neurodegeneration are present in VCP-related diseases.
“indicating the presence of non-cell autonomous mechanisms of neurodegeneration in VCP-related diseases [252].”
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- Premisecitation
Muscle from IBMPFD patients carrying VCP mutations and transgenic mice expressing VCP mutants display accumulations of SQSTM1- and LC3-positive autophagosomes and abnormal mitochondria.
“muscle from IBMPFD patients carrying VCP mutations [246] and transgenic mice expressing VCP mutants [244,248,249] display accumulations of SQSTM1- and LC3-positive autophagosomes and abnormal mitochondria [250,251].”
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Reduced levels of active/phosphorylated markers of the MTOR pathway suggest autophagy induction in SOD1G93A mice.
“reduced levels of active/phosphorylated markers of the MTOR pathway [337] suggest autophagy induction.”
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Markers of oxidative stress, ER stress, and the UPR are upregulated in spinal cords and anterior horn cells from human patients with sALS.
“Markers of oxidative stress, ER stress, and the UPR are upregulated in spinal cords and anterior horn cells from human patients with sALS [277–280].”
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Rapamycin facilitates motor neuron degeneration and rapid disease progression in SOD1G93A ALS mice.
“rapamycin facilitates motor neuron degeneration and rapid disease progression in SOD1G93A ALS mice [338]”
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- Premisecitation
iPSC-derived motor neurons harboring the ALS-associated TARDBPM337V mutation demonstrate an accumulation of insoluble mutant TARDBP at native expression levels.
“iPSC-derived motor neurons harboring the ALS-associated TARDBPM337V mutation demonstrate an accumulation of insoluble mutant TARDBP at native expression levels [298]”
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Inducing autophagy with lithium rescues SOD1G93A-related pathology and cell death.
“Inducing autophagy with lithium [361] rescues SOD1G93A-related pathology and cell death”
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Expression of TARDBPM337V in astrocytes exerts cell autonomous toxicity.
“expression of TARDBPM337V in astrocytes exerts cell autonomous toxicity [299].”
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Transplantation of SOD1G93A astrocytes into the spinal cords of wild-type mice induced motor neuron loss.
“transplantation of SOD1G93A astrocytes into the spinal cords of wild-type mice induced motor neuron loss [347].”
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TARDBPM337V increases the risk of death in iPSC-derived astrocytes.
“but also increases the risk of death in iPSC-derived astrocytes [299].”
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In a SOD1G93A transgenic mouse model of ALS, motor neurons of symptomatic animals show increased levels of LC3-II and autophagic vacuoles compared to controls or pre-symptomatic mice.
“In a SOD1G93A transgenic mouse model of ALS, motor neurons of symptomatic animals show increased levels of LC3-II and autophagic vacuoles compared to controls or pre-symptomatic mice.”
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Loss of nuclear TARDBP leads to reduced ATG7 expression.
“loss of nuclear TARDBP leads to reduced ATG7 expression [349]”
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Inhibition of MTOR reduces TARDBP aggregation and toxicity in multiple cell and animal models of ALS.
“Inhibition of MTOR likewise reduces TARDBP aggregation and toxicity in multiple cell and animal models of ALS [353,358,359].”
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Accumulations of dysmorphic and enlarged mitochondria, many with deficiencies of critical oxidative enzymes, in anterior horn cells, intramuscular nerves, and skeletal muscle are characteristic of sALS.
“Accumulations of dysmorphic and enlarged mitochondria, many with deficiencies of critical oxidative enzymes, in anterior horn cells, intramuscular nerves, and skeletal muscle are characteristic of sALS [281–285].”
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Inhibiting autophagy with 3-methyladenine impairs TARDBP degradation.
“inhibiting autophagy with 3-methyladenine impairs TARDBP degradation [352].”
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Limited overexpression of NRF2 in astrocytes mitigated neurodegeneration in SOD1G93A and SOD1H46R/H48Q mice.
“limited overexpression of NRF2 in astrocytes mitigated neurodegeneration in SOD1G93A and SOD1H46R/H48Q mice [340].”
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Transgenic expression of a C-terminal TARDBP fragment commonly associated with ALS and FTD leads to decreases in several autophagy effectors, including ATG3, ATG7, LC3, SQSTM1, and BECN1.
“Transgenic expression of a C-terminal TARDBP fragment commonly associated with ALS and FTD leads to decreases in several autophagy effectors, including ATG3, ATG7, LC3, SQSTM1, and BECN1 [351].”
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HSPB8 overexpression enhances autophagic clearance of TARDBP via elevations in TFEB, SQSTM1, and LC3.
“HSPB8 overexpression also enhances autophagic clearance of TARDBP via elevations in TFEB, SQSTM1, and LC3 [355,356].”
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TARDBP is itself involved in the regulation of autophagy.
“which is itself involved in the regulation of autophagy [276].”
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Excess mitophagy accelerates neurotoxicity and metabolic compromise in ALS models.
“excess mitophagy accelerates neurotoxicity and metabolic compromise in ALS models [363].”
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Transplantation of wild-type astrocytes into SOD1G93A rat spinal cords was neuroprotective.
“transplantation of wild-type astrocytes into SOD1G93A rat spinal cords was neuroprotective [348]”
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Autophagy dysfunction is linked to TARDBP pathology in ALS.
“Together, these findings link autophagy dysfunction to TARDBP pathology in ALS”
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Glial TARDBP inclusions predominantly reside in oligodendrocytes.
“glial TARDBP inclusions predominantly reside in oligodendrocytes [345,346]”
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Mitochondrial abnormalities, together with OPTN-positive inclusions and de novo OPTN mutations found in sALS, are suggestive of attenuated mitophagy.
“Such mitochondrial abnormalities, together with observations of OPTN-positive inclusions and de novo OPTN mutations found in sALS [286–289], are suggestive of attenuated mitophagy.”
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Accumulation of insoluble mutant TARDBP has been closely linked to neurodegeneration.
“which in previous models has not only been closely linked to neurodegeneration [297]”
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Inducing autophagy with rapamycin reduces TARDBP accumulation and mislocalization in vitro and in vivo.
“inducing autophagy with rapamycin reduces TARDBP accumulation and mislocalization in vitro [352] and in vivo [353]”
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Autophagy must operate within the contexts of localized compartments since the autophagy-lysosomal system of the soma is metabolically and temporally incapable of meeting all dendritic, axonal and synaptic demands.
“autophagy must operate within the contexts of these localized compartments since the autophagy-lysosomal system of the soma is metabolically and temporally incapable of meeting all dendritic, axonal and synaptic demands [370].”
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With global expression of germline mutations associated with ALS, neural and non-neural tissues manifest the detrimental effects of compromised autophagy, but to varying extents.
“with global expression of germline mutations associated with ALS, neural and non-neural tissues manifest the detrimental effects of compromised autophagy [11], but to varying extents [365,366]”
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Ubiquitous expression of ALS-related TBK1 mutations, heterozygous TBK1 deletion, or motor neuron-specific TBK1 deletion result in loss of function phenotypes but are insufficient to produce ALS-related neurodegeneration in mice.
“Ubiquitous expression of ALS-related TBK1 mutations, heterozygous TBK1 deletion, or motor neuron-specific TBK1 deletion result in loss of function phenotypes but are insufficient to produce ALS-related neurodegeneration in mice [214,215].”
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Autophagy can accentuate axon degeneration during excitotoxic stress.
“but can also accentuate axon degeneration during excitotoxic stress [375].”
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- Premisecitation
Autophagy is activated in astrocytes to compensate for inhibition of the UPS.
“Similar to neurons [397], autophagy is activated in astrocytes to compensate for inhibition of the UPS [398].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [398] source
Not checked in the free run.
- Interpretationreasoning
The heterogeneous manifestations of autophagy dysfunction between tissues may relate to differences in autophagy regulation specific to each cell type.
“the heterogeneous manifestations of autophagy dysfunction between tissues may relate to differences in autophagy regulation specific to each cell type.”
Quote in the paperSubstantial claim - Interpretationnone given
Genetic disruption of key autophagy effectors is sufficient to cause ALS.
“Genetic disruption of key autophagy effectors is sufficient to cause ALS, highlighting the integral relationship between autophagy and neuronal survival.”
Quote in the paperNot a substantial claim - Premisecitation
Starvation is an ineffective means of stimulating autophagy in neurons, even in the face of starvation-related downregulation of neuronal MTOR signaling.
“despite serving as a potent autophagy inducer in most cell types [383], starvation is an ineffective means of stimulating autophagy in neurons, even in the face of starvation-related downregulation of neuronal MTOR signaling [370].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [370] source
Not checked in the free run.
- Premisecitation
CHMP2B mutations induce oligodendroglial pathology.
“CHMP2B mutations induce oligodendroglial pathology [267]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [267] source
Not checked in the free run.
- Premisecitation
Autophagy initiation typically begins outside of the soma, in the distal axon tip.
“Autophagy initiation typically begins outside of the soma, in the distal axon tip [370,372,373].”
Quote in the paperNot a substantial claim0 of 3 sources checked - Interpretationreasoning
Neuronal death and dysfunction occur regardless of the point at which autophagy is impaired by disease-causing mutations.
“Since neuronal death and dysfunction occur regardless of the point at which autophagy is impaired by disease-causing mutations”
Quote in the paperSubstantial claim - Interpretationreasoning
Impaired autophagy sensitizes the nervous system to key pathogenic events occurring early in ALS pathogenesis.
“These findings not only suggest that impaired autophagy sensitizes the nervous system to key pathogenic events occurring early in ALS pathogenesis”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationnone given
Individual ALS mutations affect all phases of autophagy, from early (C9orf72), intermediate (SQSTM1, CHMP2B), and late (VCP) stages of the pathway.
“individual ALS mutations affect all phases of autophagy, from early (C9orf72), intermediate (SQSTM1, CHMP2B), and late (VCP) stages of the pathway.”
Quote in the paperSubstantial claim - Premisecitation
Purkinje-specific deletion of Atg7 results in Purkinje cell-autonomous axonal dystrophy and degeneration in mice.
“Purkinje-specific deletion of Atg7 (encoding an essential E1-like enzyme required for activating ATG12, ATG8, and LC3-I) results in Purkinje cell-autonomous axonal dystrophy and degeneration in mice [376].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [376] source
Not checked in the free run.
- Premisecitation
Autophagy is necessary for maintaining the structural integrity of the axon.
“Autophagy is also necessary for maintaining the structural integrity of the axon [375]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [375] source
Not checked in the free run.
- Premisecitation
VCP mutations cause extensive cardiac and skeletal muscle pathology.
“VCP mutations cause extensive cardiac and skeletal muscle pathology [248].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [248] source
Not checked in the free run.
- Premisecitation
Neurons must maintain protein homeostasis for the entire lifespan of an organism due to their extended post-mitotic state and lack of renewal and replacement.
“Another critical factor that uniquely impacts neuronal autophagy is the requirement of neurons to maintain protein homeostasis for the entire lifespan of an organism; this arises from the extended post-mitotic state of neurons, and the lack of their renewal and replacement [371].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [371] source
Not checked in the free run.
- Interpretationreasoning
Enhancing flux through the autophagy pathway as a whole is indispensable for preventing neurodegeneration.
“enhancing flux through the pathway as a whole is indispensable for preventing neurodegeneration.”
Quote in the paperSubstantial claim - Premisecitation
SQSTM1 mutations affect muscle, bone, and liver.
“SQSTM1 mutations affect muscle, bone, and liver [125,367,368]”
Quote in the paperNot a substantial claim0 of 3 sources checked - Interpretationreasoning
Neuroinflammation is important in ALS disease progression.
“but also highlight the importance of neuroinflammation in disease progression [215].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [215] source
Not checked in the free run.
- Interpretationreasoning
Unknown, cell type-specific pathways regulate autophagy in neurons.
“These observations imply the presence of unknown, cell type-specific pathways regulating autophagy in neurons [388].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [388] source
Not checked in the free run.
- Premisecitation
In the context of neurodegeneration, astrocytes take up aggregate-prone MAPT/tau, amyloid beta (Aβ) and SNCA (synuclein alpha), and degrade these proteins through autophagy.
“In the context of neurodegeneration, astrocytes take up aggregate-prone MAPT/tau, amyloid beta (Aβ) and SNCA (synuclein alpha), and degrade these proteins through autophagy [407–412].”
Quote in the paperNot a substantial claim0 of 6 sources checked- cites [407] source
Not checked in the free run.
- cites [408] Nielsen HM, 2009, Glia source
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- cites [409] Wyss-Coray T, 2003, Nat Med source
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- cites [410] source
Not checked in the free run.
- cites [411] Braidy N, 2013, Transl Neurodegener source
Not checked in the free run.
- cites [412] source
Not checked in the free run.
- Premisecitation
MTOR-independent activation of autophagy with benzoxazines takes place in neurons but not astrocytes.
“whereas MTOR-independent activation of autophagy with benzoxazines (e.g., 10-NCP and fluphenazine) takes place in neurons but not astrocytes [11].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [11] source
Not checked in the free run.
- Premisecitation
Conditioned media from SOD1-expressing astrocytes is toxic to cultured human motor neurons in vitro.
“conditioned media from SOD1-expressing astrocytes is toxic to cultured human motor neurons in vitro [181,415]”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Microglia actively clear apoptotic cells, myelin and synaptic debris, axonal fragments and protein deposits from the CNS through phagocytosis.
“Microglia actively clear apoptotic cells, myelin and synaptic debris, axonal fragments and protein deposits from the CNS through phagocytosis [428–430].”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation
In neurodegenerative diseases, microglial activation may accentuate neuron loss by promoting and propagating regional and local neuroinflammation.
“In neurodegenerative diseases, microglial activation may accentuate neuron loss by promoting and propagating regional and local neuroinflammation [420,421].”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
Loss of function mutations in TREM2 are risk factors for ALS.
“loss of function mutations in TREM2 (triggering receptor expressed on myeloid cells 2), which affect microglia phagocytosis and inflammation, are risk factors for ALS [425–427]”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation
Reactive astrocytes from SOD1 transgenic mice secrete TGFB1, which stimulates MTOR signaling and impairs autophagy in co-cultured motor neurons.
“reactive astrocytes from SOD1 transgenic mice secrete TGFB1, which stimulates MTOR signaling and impairs autophagy in co-cultured motor neurons [415]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [415] source
Not checked in the free run.
- Interpretationcitation
Elevated macrophage markers in ALS CSF are presumably due to increased CNS microglia or their activation.
“presumably due to increased CNS microglia or their activation, as suggested by positron emission tomography (PET) imaging using radiotracers specific for activated microglia [423,424].”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationcitation
Astrocytes can exacerbate neuronal toxicity by compromising neuronal proteostasis in a non-cell autonomous fashion.
“suggesting that astrocytes can exacerbate neuronal toxicity by compromising neuronal proteostasis in a non-cell autonomous fashion.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [415] source
Not checked in the free run.
- Premisecitation
Selective clearance of SOD1-positive inclusions from astrocytes is sufficient to slow disease progression.
“Selective clearance of SOD1-positive inclusions from astrocytes is sufficient to slow disease progression [414]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [414] source
Not checked in the free run.
- Premisecitation
ALS patients exhibit elevated macrophage markers in their CSF compared to unaffected controls.
“ALS patients exhibit elevated macrophage markers in their CSF compared to unaffected controls [422]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [422] source
Not checked in the free run.
- Premisecitation
In mutant SOD1 transgenic mice, continued unabridged neuroinflammation enhances neurodegeneration and accelerates disease progression.
“however, with time the continued and unabridged neuroinflammation only enhances neurodegeneration and accelerates disease progression [434–436].”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
In contrast to neurons, MTOR inhibition and starvation robustly activate autophagy in astrocytes.
“In contrast to neurons, MTOR inhibition and starvation robustly activate autophagy in astrocytes [402]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [402] Kulkarni A, 2019, Autophagy.
Not checked in the free run.
- Interpretationcitation
Activation of CNS microglia and astrocytes and the subsequent production of pro-inflammatory cytokines and interleukins (neuroinflammation) is intricately connected to ALS pathogenesis.
“The activation of CNS microglia and astrocytes, and the subsequent production of pro-inflammatory cytokines and interleukins (neuroinflammation), is intricately connected to ALS pathogenesis.”
Quote in the paperNot a substantial claim - Premisecitation
Unlike neurons, astrocytic loss of Atg7 or Atg5 is insufficient to cause cell death or the accumulation of misfolded and ubiquitinated proteins.
“Unlike neurons, astrocytic loss of Atg7 or Atg5 is insufficient to cause cell death or the accumulation of misfolded and ubiquitinated proteins [380,381]”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
In pre-symptomatic mutant SOD1 transgenic mice, activated microglia initially display neuroprotective properties that slow disease progression.
“In pre-symptomatic mutant SOD1 transgenic mice, activated microglia initially display neuroprotective properties that slow disease progression;”
Quote in the paperNot a substantial claim0 of 3 sources checked - Interpretationreasoning
Astrocytes have greater proteostatic reserve compared to neurons.
“implying greater proteostatic reserve in astrocytes compared to neurons.”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Microglial phagocytosis of Aβ deposits in Alzheimer disease models requires the autophagy-related factors BECN1, ATG7 and LC3.
“microglial phagocytosis of Aβ deposits in Alzheimer disease models [430,431] requires the autophagy-related factors BECN1, ATG7 and LC3 [432,433].”
Quote in the paperNot a substantial claim0 of 4 sources checked - Interpretationcitation
Microglia play a pivotal role in ALS pathogenesis.
“confirming the pivotal role played by microglia in ALS pathogenesis.”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
ALS patients carrying C9orf72 mutations display microglial activation that correlates with disease progression.
“ALS patients carrying C9orf72 mutations display microglial activation that correlates with disease progression [438].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [438] source
Not checked in the free run.
- Premisecitation
Oligodendrocytes in ALS patients have lower levels of SLC16A1/MCT1, an essential lactate transporter in the CNS.
“and lower levels of SLC16A1/MCT1 (solute carrier family 16 member 1), an essential lactate transporter in the CNS whose expression is regulated by autophagy [458].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [458] source
Not checked in the free run.
- Interpretationreasoning
Oligodendrocyte autophagy may play a necessary but insufficient role in post-injury repair of the spinal cord.
“These observations suggest that oligodendrocyte autophagy may play a necessary but insufficient role in post-injury repair of the spinal cord [453],”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [453] source
Not checked in the free run.
- Premisecitation
Oligodendrocytes in ALS patients demonstrate inclusions containing TARDBP and FUS.
“Separately, oligodendrocytes in ALS patients demonstrate inclusions containing TARDBP and FUS [455–457]”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Autophagic activity increases during progenitor cell differentiation into mature oligodendrocytes.
“Autophagic activity increases during progenitor cell differentiation into mature oligodendrocytes [444].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [444] Bankston AN, 2019, Glia source
Not checked in the free run.
- Premisecitation
Expression of SLC16A1/MCT1 is regulated by autophagy.
“an essential lactate transporter in the CNS whose expression is regulated by autophagy [458].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [458] source
Not checked in the free run.
- Interpretationcitation
Excessive autophagy in oligodendrocytes may lead to neuronal toxicity in a non-cell autonomous manner.
“but excessive autophagy in oligodendrocytes may lead to neuronal toxicity in a non-cell autonomous manner.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [453] source
Not checked in the free run.
- Premisecitation
ALS-associated mutations in TBK1, OPTN, SQSTM1, and VCP all affect autophagy as well as microglial function and innate immunity.
“ALS-associated mutations in TBK1, OPTN, SQSTM1, and VCP all affect autophagy as well as microglial function and innate immunity [192,205,206,441–443].”
Quote in the paperSubstantial claim0 of 6 sources checked- cites [192] source
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- cites [205] source
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- cites [206] source
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- cites [441] Asai T, 2002, Jpn J Cancer Res source
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- cites [442] source
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- cites [443] source
Not checked in the free run.
- Premisecitation
During development, autophagy is required for refining and culling of Schwann cell-mediated myelination.
“During development, autophagy is required for refining and culling of Schwann cell-mediated myelination,”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [459] source
Not checked in the free run.
- Premisecitation
Loss of autophagy with oligodendrocyte-specific deletion of Atg5 impairs motor recovery after spinal cord contusion in mice.
“Loss of autophagy with oligodendrocyte-specific deletion of Atg5 impairs motor recovery after spinal cord contusion in mice [449],”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [449] source
Not checked in the free run.
- Premisecitation
In multiple system atrophy, the pathologic hallmark consists of cytoplasmic SNCA inclusions in oligodendrocytes.
“In multiple system atrophy (MSA), the pathologic hallmark consists of cytoplasmic SNCA inclusions in oligodendrocytes [12],”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [12] source
Not checked in the free run.
- Premisecitation
Myeloid-specific C9orf72 knockout recapitulates the lysosomal accumulation and hyperactive immune response phenotype.
“a phenotype recapitulated by myeloid-specific C9orf72 knockout, indicating the significance of C9orf72 in maintaining physiological immune responses [440].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [440] McCauley ME, 2020, Nature source
Not checked in the free run.
- Interpretationcitation
C9orf72 is significant in maintaining physiological immune responses.
“indicating the significance of C9orf72 in maintaining physiological immune responses [440].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [440] McCauley ME, 2020, Nature source
Not checked in the free run.
- Interpretationreasoning
These findings constitute indirect evidence for impaired oligodendrocyte autophagy in ALS.
“These findings constitute indirect evidence for impaired oligodendrocyte autophagy in ALS;”
Quote in the paperNot a substantial claim - Premisecitation
Transplanted wild-type microglia effectively extend the survival of mutant SOD1 transgenic mice.
“Transplanted wild-type microglia effectively extend the survival of mutant SOD1 transgenic mice [437],”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [437] source
Not checked in the free run.
- Premisecitation
Impaired autophagy in C9orf72-deficient myeloid cells leads to the accumulation of the pro-inflammatory STING protein.
“impaired autophagy in C9orf72-deficient myeloid cells leads to the accumulation of the pro-inflammatory STING (stimulator of interferon genes) protein [440].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [440] McCauley ME, 2020, Nature source
Not checked in the free run.
- Interpretationcitation
Microglial activation is important in ALS pathogenesis.
“confirming the importance of microglial activation in ALS pathogenesis.”
Quote in the paperSubstantial claim - Premisecitation
Accumulation of SNCA inclusions in oligodendrocytes is exacerbated by autophagy inhibition, either pharmacologically with chloroquine or genetically by MIR101 overexpression.
“and the accumulation of these inclusions is exacerbated by autophagy inhibition, either pharmacologically with chloroquine or genetically by MIR101 overexpression [12,450,454].”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation
Autosomal dominant FIG4 mutations are associated with rare forms of familial ALS.
“Autosomal dominant FIG4 mutations are associated with rare forms of familial ALS [470],”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [470] source
Not checked in the free run.
- Interpretationreasoning
Deviation from normal proteostasis results in muscle pathology.
“In either case, deviation from normal proteostasis results in muscle pathology.”
Quote in the paperSubstantial claim - Premisecitation
Abnormal Schwann cell autophagy is observed in dysmyelinating forms of inherited polyneuropathies.
“Abnormal Schwann cell autophagy is also observed in dysmyelinating forms of inherited polyneuropathies.”
Quote in the paperNot a substantial claim - Premisecitation
A protective response mounted by RUNX1 limits muscle wasting after denervation by suppressing autophagy.
“such a protective response (mounted by the transcription factor RUNX1) limits muscle wasting after denervation by suppressing autophagy.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [472] source
Not checked in the free run.
- Premisecitation
The effects of skeletal muscle-specific SOD1G93A expression are mitigated by siRNA-mediated MAP1LC3B knockdown and subsequent reduction of autophagy flux.
“but these effects are mitigated by siRNA-mediated MAP1LC3B knockdown and the subsequent reduction of autophagy flux [479].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [479] source
Not checked in the free run.
- Premisecitation
PPARGC1A/PGC1A overexpression drives non-MTOR-dependent autophagy by increasing TFEB nuclear localization in dystrophin-deficient muscle fibers.
“Moreover, PPARGC1A/PGC1A (PPARG coactivator 1A) overexpression drives non-MTOR-dependent autophagy by increasing TFEB nuclear localization in dystrophin-deficient muscle fibers [19];”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [19] Spaulding HR, 2020, Physiol Rep source
Not checked in the free run.
- Premisecitation
Exercise triggers autophagy by activating ULK1 and dissociating BCL2 from BECN1, thereby disinhibiting the initiation complex.
“Exercise triggers autophagy by activating ULK1 and dissociating BCL2 from BECN1, thereby disinhibiting the initiation complex [484,485].”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationcitation
Higher JUN/c-Jun in CMT1A may be part of a compensatory, neuroprotective response to the pathogenic effects of the PMP22 duplication.
“which may be part of a compensatory, neuroprotective response to the pathogenic effects of the PMP22 duplication [467–469].”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation
In Charcot-Marie-Tooth type 1A caused by duplication of PMP22, Schwann cell autophagy is aberrantly elevated.
“in Charcot-Marie-Tooth (CMT) type 1A caused by duplication of PMP22 (peripheral myelin protein 22), Schwann cell autophagy is aberrantly elevated”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation
Remyelination after peripheral nerve injury is hindered by injury-induced upregulation of microRNA Mir195a, which inhibits Atg14 and suppresses Schwann cell autophagy.
“Remyelination after peripheral nerve injury is hindered by injury-induced upregulation of the microRNA Mir195a, which inhibits Atg14 and, in turn, suppresses Schwann cell autophagy [14,15].”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
Myelinophagy is impaired by Schwann cell-specific Atg7 deletion.
“and this function is impaired by Schwann cell-specific Atg7 deletion [459,464].”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
Enhancing autophagy in mouse models of Duchenne muscular dystrophy pharmacologically with rapamycin or AICAR improves muscle strength and contractility.
“In contrast, enhancing autophagy in mouse models of Duchenne muscular dystrophy (DMD) pharmacologically with rapamycin or 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR, an AMP analog which stimulates AMPK) improves muscle strength and contractility [480,481].”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationreasoning
Inefficient myelinophagy may result in the loss of motor neurons and muscle atrophy.
“suggesting that inefficient myelinophagy may result in the loss of motor neurons and muscle atrophy.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [470] source
Not checked in the free run.
- Premisecitation
Autophagy inhibition with 3-methyladenine blunts recovery in mice after myotoxic injury.
“since autophagy inhibition with 3-methyladenine blunts recovery in mice after myotoxic injury [475].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [475] source
Not checked in the free run.
- Interpretationcitation
Autophagy appears to be required for muscle regeneration.
“Autophagy appears to be required for muscle regeneration, since autophagy inhibition with 3-methyladenine blunts recovery in mice after myotoxic injury [475].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [475] source
Not checked in the free run.
- Premisecitation
In muscle biopsies from human volunteers after endurance exercise, measurements of autophagy markers revealed downregulated AKT and MTOR signaling, elevated ATG5, ATG12, and LC3-II.
“In muscle biopsies collected from human volunteers after endurance exercise, measurements of autophagy markers revealed downregulated AKT and MTOR signaling, elevated ATG5, ATG12, and LC3-II [486].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [486] source
Not checked in the free run.
- Premisecitation
Vastus lateralis biopsies from human runners after a 200-kilometer race showed increased transcription of autophagy factors ATG4B, ATG12, GABARAPL1, LC3B, CSTL, BNIP3, and BNIP3L.
“Similarly, vastus lateralis biopsies taken from human runners after a 200-kilometer race showed increased transcription of autophagy factors ATG4B, ATG12, GABARAPL1, LC3B, CSTL (cathepsin L), BNIP3, and BNIP3L [487],”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [487] source
Not checked in the free run.
- Premisecitation
In CMT1A, elevated Schwann cell autophagy is associated with higher levels of JUN/c-Jun.
“and associated with higher levels of JUN/c-Jun,”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisenone given
Inherited myopathies demonstrate muscle pathology that includes markers of elevated autophagy.
“In addition, inherited myopathies demonstrate muscle pathology that includes markers of elevated autophagy.”
Quote in the paperNot a substantial claim - Premisecitation
In CMT4J, autosomal recessive mutations in FIG4 lead to incompetent myelinophagy.
“In CMT4J, autosomal recessive mutations in the gene encoding FIG4, a phosphatase required for recycling phosphoinositides involved in vesicle trafficking, lead to incompetent myelinophagy [13].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [13] source
Not checked in the free run.
- Premisecitation
After nerve injury, Schwann cells oversee the capture of myelin debris in autophagosomes in a process termed myelinophagy.
“After nerve injury, Schwann cells oversee the capture of myelin debris in autophagosomes in a process termed “myelinophagy” [459,462,463],”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation
ulk1 knockout impairs muscle regeneration in zebrafish.
“Similarly, ulk1 knockout impairs muscle regeneration in zebrafish [476],”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [476] source
Not checked in the free run.
- Premisereasoning
There is conflicting evidence as to whether autophagy contributes to or mitigates muscle atrophy in ALS.
“There is conflicting evidence as to whether autophagy contributes to or mitigates muscle atrophy in ALS.”
Quote in the paperNot a substantial claim - Premisecitation
Conditional Atg5 deletion in mouse skeletal muscle leads to accumulation of ubiquitin-positive inclusions and ultrastructural disorganization.
“Analogously, conditional Atg5 deletion in mouse skeletal muscle leads to accumulation of ubiquitin-positive inclusions and ultrastructural disorganization [478].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [478] source
Not checked in the free run.
- Interpretationcitation
Increased transcription of autophagy factors after a 200-kilometer race may be an adaptive response to muscle injury related to long-distance running.
“which may be an adaptive response to muscle injury related to long-distance running.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [487] source
Not checked in the free run.
- Premisenone given
Traditional measures relying upon accumulation of pathway intermediates such as LC3-II cannot discriminate between true induction and late-stage inhibition of autophagosome maturation.
“Traditional measures relying upon the accumulation of pathway intermediates such as LC3-II cannot discriminate between true induction and late-stage inhibition of autophagosome maturation”
Quote in the paperSubstantial claim - Premisenone given
With the exception of 10-NCP, MTOR-independent strategies have been tested almost exclusively in non-neuronal model systems.
“Notably, with the exception of 10-NCP, the above strategies have been tested almost exclusively in non-neuronal model systems.”
Quote in the paperSubstantial claim - Interpretationreasoning
Such pleiotropy leads to well-documented and multi-systemic toxicities, especially with long-term use.
“Such pleiotropy leads to well-documented and multi-systemic toxicities, especially with long-term use;”
Quote in the paperSubstantial claim - Premisecitation
10-NCP and related compounds are capable of inducing neuronal autophagy through an MTOR- and AKT-independent signaling cascade.
“10-NCP and related compounds are also capable of inducing neuronal autophagy through an MTOR- and AKT-independent signaling cascade [357,384].”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Age-related declines in MFN2, together with mitochondrial fragmentation and fission machinery in muscle, indicate inefficient mitophagic flux in aging muscle.
“Age-related declines in MFN2 (mitofusin 2), which is associated with macroautophagy and mitophagy [492], together with mitochondrial fragmentation and mitochondrial fission machinery in muscle, indicate inefficient mitophagic flux in aging muscle [493].”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisenone given
Rapalogs have wide-ranging effects targeting myriad cellular pathways, including growth signaling, translation, stress responses, transcriptional regulation, and cytoskeletal remodeling.
“and their wide-ranging effects target myriad cellular pathways, including growth signaling, translation, stress responses, transcriptional regulation, and cytoskeletal remodeling (left).”
Quote in the paperSubstantial claim - Premisenone given
Inhibitors of MTOR (rapalogs) only weakly activate autophagy in neurons.
“Inhibitors of MTOR inhibitors (rapalogs) only weakly activate autophagy in neurons,”
Quote in the paperNot a substantial claim - Premisecitation
These age-related changes in aged rats were reduced with chronic and forced contractile activity induced by implanted stimulators.
“these changes were reduced with chronic and forced contractile activity induced by implanted stimulators [497].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [497] source
Not checked in the free run.
- Premisecitation
Exercise potentiates autophagy activation due to starvation and the resulting reduction in plasma insulin, which downregulates AKT and FOXO3 signaling.
“Exercise also potentiates autophagy activation due to starvation and the resulting reduction in plasma insulin, which in turn downregulates AKT and FOXO3 signaling [16,18].”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
A phase II trial of rapamycin (sirolimus) for ALS patients began in 2018.
“Autophagy induction using MTOR inhibitors is currently being tested in ALS – a phase II trial of rapamycin (sirolimus) for ALS patients began in 2018 [498].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [498] source
Not checked in the free run.
- May combine two claims. 127
- Classified as probably not a substantial claim. 31
May combine two claims.
PremisecitationAutophagy is regulated by distinct mechanisms in different cell types, and these cell type-specific mechanisms underlie the differential vulnerability of separate tissues to autophagy mutations, resulting in heterogeneous manifestations of disease.
“Furthermore, mounting evidence shows that autophagy is regulated by distinct mechanisms in different cell types [11–26], and these cell type-specific mechanisms underlie the differential vulnerability of separate tissues to autophagy mutations, resulting in heterogenous manifestations of disease.”
Quote in the paperSubstantial claim0 of 10 sources checked- cites [11] source
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- cites [12] source
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- cites [13] source
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- cites [14] source
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- cites [15] source
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- cites [16] source
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- cites [17] source
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- cites [18] source
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- cites [19] Spaulding HR, 2020, Physiol Rep source
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- cites [20] source
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMacroautophagy is an evolutionarily conserved eukaryotic pathway for bulk and selective degradation of proteins and organelles.
“Macroautophagy, often referred to simply as autophagy, is an evolutionarily conserved eukaryotic pathway for bulk and selective degradation of proteins and organelles [31].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [31] source
Not checked in the free run.
May combine two claims.
PremisecitationALS-FTD-associated SQSTM1 mutations frequently affect the UBA and LIR domains involved in autophagy and include both missense and nonsense mutations.
“ALS-FTD-associated SQSTM1 mutations frequently affect the UBA and LIR domains involved in autophagy and include both missense and nonsense mutations [123–125].”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationOverexpression of SQSTM1 variants carrying disease-associated mutations in the UBA domain exhibits a PDB-like skeletal disorder and impaired spatial learning and long-term memory.
“On the other hand, overexpression of SQSTM1 variants carrying disease-associated mutations in the UBA domain exhibit a PDB-like skeletal disorder [138,139] as well as impaired spatial learning and long-term memory [140].”
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PremisecitationInitiation of autophagosome formation begins with dissociation of MTOR from the phagophore assembly site, cued by nutrient starvation or treatment with rapamycin or its derivatives.
“The initiation step begins with the dissociation of MTOR (mechanistic target of rapamycin kinase) from the PAS, cued by nutrient starvation or treatment with rapamycin or its various derivatives [36,37].”
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PremisecitationFusion of autophagosomes with lysosomes is mediated by the HOPS complex, whose subunits include VPS11, VPS16, VPS18, VPS33A, VPS39, and VPS41.
“Fusion of the autophagosome and lysosome is mediated by the homotypic fusion and protein sorting (HOPS) complex, whose subunits include VPS11, VPS16, VPS18, VPS33A, VPS39, and VPS41 [45,46].”
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PremisecitationTBK1 amplifies mitophagy signaling by phosphorylating OPTN and SQSTM1, enhancing their binding to ubiquitin and LC3, and promoting TBK1 autophosphorylation in a positive-feedback manner.
“Additionally, TBK1 amplifies the signaling cascade for mitophagy by phosphorylating OPTN and SQSTM1 (which enhances binding to ubiquitin and LC3) and promoting TBK1 autophosphorylation in a positive-feedback manner [58,59].”
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PremisecitationUnaffected individuals carry 2-30 repeated GGGGCC stretches within the first intron of C9orf72, whereas patients with C9orf72-associated ALS-FTD harbor several hundred to thousands of repeats.
“Unaffected individuals carry 2–30 repeated stretches of GGGGCC within the first intron of the gene, but patients with C9orf72-associated ALS-FTD harbor several hundred to thousands of repeats [141,142].”
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PremisecitationLC3-I undergoes proteolytic processing by ATG4 and conjugation to phosphatidylethanolamine through ATG7 and ATG3 to form lipidated LC3-II, which is incorporated into the phagophore membrane.
“Before membrane insertion, the unbound and immature LC3 precursor protein (LC3-I) undergoes proteolytic processing by ATG4, and conjugation to phosphatidylethanolamine through ATG7 and ATG3. The resulting mature, lipidated isoform (LC3-II) is incorporated into the phagophore membrane [41].”
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PremisecitationKnockdown of the SQSTM1 ortholog in zebrafish leads to an ALS-like phenotype consisting of locomotor and motor neuron axonal abnormalities, which is rescued by overexpression of wild-type human SQSTM1 or rapamycin.
“Knockdown of the SQSTM1 ortholog in zebrafish leads to an ALS-like phenotype consisting of locomotor and motor neuron axonal abnormalities. Overexpression of wild-type human SQSTM1 or application of the autophagy activator rapamycin rescues these phenotypes [137].”
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PremisecitationSQSTM1 mutations are a rare cause of ALS-FTD, accounting for ~1-3.5% of cases with or without family history, and also cause Paget's disease of bone and inclusion body myositis.
“SQSTM1 mutations are not only a rare cause of ALS-FTD, accounting for ~1-3.5% of cases with or without family history [123–125], but also Paget’s disease of bone (PDB), a chronic and progressive skeletal disorder characterized by disorganized bone turnover [126,127], and inclusion body myositis (IBM) [128].”
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PremisecitationSQSTM1 mutations affecting the UBA domain impair ubiquitin recognition, whereas mutations within the LIR domain impact LC3 recognition and substrate delivery to autophagosomes.
“SQSTM1 mutations affecting the UBA domain impair ubiquitin recognition [130], whereas mutations within the LIR domain impact LC3 recognition and substrate delivery to the autophagosomes [84,131].”
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PremisecitationTFEB directs expression of autophagy and lysosomal genes comprising the CLEAR network by binding to a conserved promoter motif.
“Global regulation of the myriad effectors and phases of autophagy is overseen by TFEB (transcription factor EB), a basic helix-loop-helix leucine zipper that directs expression of autophagy and lysosomal genes comprising the coordinated lysosomal expression and regulation (CLEAR) network by binding to a conserved promoter motif [47,48].”
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PremisecitationSQSTM1-positive inclusions are found in the majority of patients with ALS and FTD and often overlap with inclusions that stain for ubiquitin and TARDBP/TDP-43.
“Furthermore, SQSTM1-positive inclusions are found in the majority of patients with ALS and FTD, and often overlap with inclusions that stain for ubiquitin and TARDBP/TDP-43 (TAR DNA binding protein), an essential RNA-binding protein integrally connected with ALS-FTD [82,116–118] (Figure 1).”
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InterpretationcitationMolecular and histopathologic analyses of patient tissues demonstrate mislocalized or accumulated autophagy machinery, pathogenic mutations underlying familial neurodegenerative diseases disable known autophagy-related factors, and genetically ablating autophagy effectors produces neurodegeneration in cell and animal model systems, supporting a role for autophagy dysfunction in age-related neurode
“Molecular and histopathologic analyses of patient tissues demonstrate mislocalized or accumulated autophagy machinery, pathogenic mutations underlying familial neurodegenerative diseases disable known autophagy-related factors, and genetically ablating autophagy effectors produce neurodegeneration in cell and animal model systems [74–81], supporting a role for autophagy dysfunction in the devel”
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- cites [80] source
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Premisecitationsqstm1-knockout mice display reduced numbers of osteoclasts, cognitive impairment, and anxiety, associated with hyperphosphorylated MAPT/tau and neurofibrillary tangles.
“sqstm1-knockout mice display reduced numbers of osteoclasts as well as cognitive impairment and anxiety, associated with hyperphosphorylated MAPT/tau and neurofibrillary tangles [134–136].”
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PremisecitationNucleation of the nascent phagophore is orchestrated by a class III phosphatidylinositol 3-kinase complex containing BECN1, PIK3C3/VPS34, PIK3R4/p150, NRBF2 and either ATG14 or UVRAG.
“Next, nucleation of the nascent phagophore is orchestrated by a class III phosphatidylinositol 3-kinase (PtdIns3K) complex containing BECN1, PIK3C3/VPS34, PIK3R4/p150, NRBF2 and either ATG14 or UVRAG [38,39].”
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PremisecitationDegradation of neuronal mitochondria can occur non-cell autonomously, as demonstrated by astrocytic engulfment and degradation of mitochondria excreted from retinal ganglion cells.
“Interestingly, degradation of neuronal mitochondria can occur in a non-cell autonomous fashion, as demonstrated by the astrocytic engulfment and degradation of mitochondria excreted from retinal ganglion cells [60].”
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PremisecitationExpansion of the phagophore membrane is guided by the ATG12-ATG5-ATG16L1 complex, which catalyzes insertion of LC3 into the phagophore membrane.
“Expansion then occurs through maturation of the extending phagophore membrane guided by the ATG12–ATG5-ATG16L1 complex, catalyzing insertion of MAP1LC3/LC3 (microtubule associated protein 1 light chain 3) into the phagophore membrane [40,41].”
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PremisecitationDeletion of the mouse C9orf72 ortholog leads to splenomegaly, lymphadenopathy, dysregulation of macrophages and microglia, and excess production of inflammatory cytokines.
“In contrast, deletion of the mouse C9orf72 ortholog leads to splenomegaly, lymphadenopathy, dysregulation of macrophages and microglia, and excess production of inflammatory cytokines [184–187].”
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InterpretationcitationConditioned medium from astrocytes differentiated from patient-derived iPSC lines (two with C9orf72 expansion mutations) applied to HEK293T cells reduces LC3-II while increasing SQSTM1 levels, suggesting non-cell autonomous inhibition of autophagy by astrocytes in ALS.
“In addition, conditioned medium from astrocytes differentiated from patient-derived iPSC lines (two of which harbor C9orf72 expansion mutations) applied to HEK293T cells reduces LC3-II while increasing SQSTM1 levels [181], suggesting non-cell autonomous inhibition of autophagy by astrocytes in ALS.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [181] Madill M, 2017, Mol Brain source
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PremisecitationTBK1 is a cytoplasmically-localized homodimeric multidomain protein with an ubiquitin-like domain, an N-terminal serine/threonine kinase domain, and two coiled-coil domains.
“TBK1/NAK/T2K (TANK binding kinase 1) is a cytoplasmically-localized homodimeric multidomain protein with an ubiquitin-like domain, a N-terminal serine/threonine kinase domain, and two coiled-coil domains [192].”
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Premisecitationc9orf72 knockout in mouse enhances autophagy by de-repressing MTOR and increasing TFEB nuclear translocation.
“Paradoxically, however, c9orf72 knockout in mouse (which models the loss of function attributed to the hexanucleotide repeat expansion) enhances autophagy by de-repressing MTOR and, in turn, increasing TFEB nuclear translocation [179,180].”
Quote in the paperNot a substantial claim0 of 2 sources checked- The authors state this as an assumption: c9orf72 knockout in mouse models the loss of function attributed to the C9orf72 hexanucleotide repeat expansion.
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Premisecitationc9orf72 knockout animals exhibit a shortened lifespan, but no specific neuronal defects have been identified in these mice.
“While c9orf72 knockout animals exhibit a shortened lifespan [184,185,187], no specific neuronal defects have been identified in these mice.”
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PremisecitationThe C9orf72 protein belongs to the DENN family and binds the GTPases RAB7 and RAB11, which are involved in endosome maturation and recycling.
“The C9orf72 protein belongs to the DENN (differentially expressed in normal and neoplastic cells) family [143,144] and binds the GTPases RAB7 and RAB11, which are involved in endosome maturation and recycling [145].”
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PremisecitationTBK1 is expressed in all tissues, but at much higher levels in neurons of the hippocampus, cortex and lateral ventricle, with moderate levels in glial cells of the cortex and cerebellum.
“TBK1 is expressed in all tissues, but at much higher levels in neurons of the hippocampus, cortex and lateral ventricle. Moderate levels of the protein have been detected in the glial cells of the cortex and cerebellum [193].”
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InterpretationcitationDeletion of the zebrafish and C. elegans homologs of C9orf72 results in impaired locomotion and motor axon degeneration, implying that the C9orf72 protein is essential for motor neuron function and survival in these systems.
“Deletion of the zebrafish and C. elegans homologs of C9orf72 results in impaired locomotion and motor axon degeneration [182,183], implying that the C9orf72 protein is essential for motor neuron function and survival in these systems.”
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InterpretationreasoningC9orf72 assists in the formation of nascent autophagosomes, consistent with impaired autophagy observed in murine cortical neurons and human iPSC-derived neurons upon C9orf72 knockdown.
“Together, these findings suggest that C9orf72 assists in the formation of nascent autophagosomes, consistent with the finding of impaired autophagy in murine cortical neurons [148] and human iPSC-derived neurons [154] upon C9orf72 knockdown.”
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PremisecitationC9orf72 expansion mutations are associated with ALS/FTLD and also with symptoms reminiscent of Parkinson disease, Alzheimer disease, Huntington disease, and corticobasal syndrome.
“For instance, C9orf72 expansion mutations are associated not only with ALS/FTLD, but also with symptoms reminiscent of Parkinson disease, Alzheimer disease, Huntington disease, and corticobasal syndrome, reinforcing the imperfect connection between clinical and molecular phenotypes and emphasizing the need for molecular diagnostics [155–164].”
Quote in the paperNot a substantial claim0 of 10 sources checked- cites [155] Anor CJ, 2015, Neurobiol Aging
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- cites [157] Cacace R, 2013, Neurobiol Aging source
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- cites [158] Harms M, 2013, JAMA Neurol source
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- cites [159] Kostić VS, 2014, J Neurol source
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- cites [160] Lesage S, 2013, Brain source
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- cites [161] source
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- cites [162] source
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- cites [163] O’Dowd S, 2012, Mov Disord source
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- cites [164] Hensman Moss DJ, 2014, Neurology source
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PremisecitationC9orf72 forms a complex with SMCR8 and WDR41, which targets the complex to lysosomes and interacts with RB1CC1-ULK1-ATG13-ATG101 to regulate autophagosome formation.
“C9orf72 also forms a complex with SMCR8, a guanine nucleotide exchange factor, and WDR41, a WD40 protein essential for targeting the C9orf72-SMCR8-WDR41 complex to lysosomes [146–150]. Here, this complex interacts with RB1CC1-ULK1-ATG13-ATG101, which together are involved in autophagosome formation [149].”
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PremisecitationC9orf72 mutations are associated with reduced basal autophagy and enhanced sensitivity to autophagy inhibitors in human iPSC-derived neurons.
“C9orf72 mutations are associated with reduced basal autophagy and enhanced sensitivity to autophagy inhibitors in human iPSC-derived neurons [153,178].”
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InterpretationcitationDPR inclusions rarely co-label with TARDBP pathological inclusions and are mainly found in areas of the CNS that are not pathologically affected, arguing against a direct role for DPRs in neurodegeneration.
“On the other hand, DPR inclusions rarely co-label with TARDBP pathological inclusions and are mainly found in areas of the CNS that are not pathologically affected [171,174–177], arguing against a direct role for DPRs in neurodegeneration.”
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- cites [174] Davidson Y, 2016, Neuropathol Appl Neurobiol source
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- cites [175] source
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- cites [176] Gomez-Deza J, 2015, Acta Neuropathol Commun source
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- cites [177] source
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PremisecitationNeurons derived from iPSCs carrying the C9orf72 repeat expansion recapitulate key features of cellular pathology associated with ALS, including hyperexcitability and decreased viability upon exposure to excitotoxic agents such as glutamate.
“Further, neurons derived from iPSCs carrying the C9orf72 repeat expansion recapitulate key features of cellular pathology associated with ALS, including hyperexcitability [154,188,189] and decreased viability upon exposure to excitotoxic agents such as glutamate [154,190,191].”
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PremisecitationVCP/p97/Cdc48 is involved in DNA replication and repair, cell cycle regulation, and protein clearance.
“VCP/p97/Cdc48 (valosin containing protein) is involved in a wide range of essential cellular processes, including DNA replication and repair, cell cycle regulation, and protein clearance [238,239].”
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PremisecitationIn vitro, silencing of TBK1 or ALS-related TBK1 variants reduces the recruitment of OPTN and LC3B to damaged mitochondria, thereby impairing mitophagy and resulting in the accumulation of defective mitochondria.
“In vitro, silencing of TBK1 or ALS-related TBK1 variants reduces the recruitment of OPTN and LC3B to damaged mitochondria [212,213], thereby impairing mitophagy and resulting in the accumulation of defective mitochondria (Figure 1).”
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PremisecitationTBK1 phosphorylates SMCR8, which forms a complex with C9orf72 and WDR41, thereby enhancing autophagy initiation.
“TBK1 also phosphorylates SMCR8, which forms a complex with C9orf72 and WDR41, thereby enhancing autophagy initiation [148].”
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InterpretationcitationIn neurons, TBK1 knockdown enhances the accumulation of SQSTM1, which can be rescued by phosphomimetic SMCR8 mutations, suggesting that SMCR8 phosphorylation is crucial for TBK1's effects on autophagy.
“In neurons, TBK1 knockdown enhances the accumulation of SQSTM1, which can be rescued by phosphomimetic SMCR8 mutations [148], suggesting that SMCR8 phosphorylation is crucial for TBK1’s effects on autophagy.”
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PremisecitationGenetic loss of ATG5 exacerbates mutant FUS impairment of stress granule clearance, enhancing stress granule accumulation and leading to cell death.
“this effect is exacerbated by genetic loss of ATG5, enhancing stress granule accumulation and, ultimately, leading to cell death [235].”
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InterpretationreasoningTBK1 loss of function also prolongs the disease course by reducing neuroinflammation, suggesting that the dual functions of TBK1 in autophagy and inflammation independently and inversely impact ALS pathogenesis.
“Unexpectedly, however, TBK1 loss of function also prolongs the disease course by reducing neuroinflammation, suggesting that the dual functions of TBK1 in autophagy and inflammation independently and inversely impact ALS pathogenesis.”
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PremisecitationRapamycin-mediated activation of autophagy ameliorates mutant FUS-induced stress granule accumulation and cell death.
“Conversely, rapamycin-mediated activation of autophagy ameliorates these features, suggesting that FUS-positive inclusions are autophagy substrates [235].”
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InterpretationcitationNeuropathological analysis of CNS tissue from ALS patients with TBK1 mutations shows SQSTM1- and TARDBP-positive inclusions in motor neurons and glia, along with reduced TBK1 mRNA and protein, suggesting haploinsufficiency mechanisms.
“Neuropathological analysis of CNS tissue from ALS patients with TBK1 mutations shows SQSTM1- and TARDBP-positive inclusions in motor neurons and glia [206,210,211], along with reduced TBK1 mRNA and protein, suggesting haploinsufficiency mechanisms [205,206].”
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PremisecitationThe majority of disease-associated FUS mutations affect the C-terminal nuclear localization signal, resulting in cytosolic mislocalization and aggregation of mutant FUS.
“The majority of disease-associated FUS mutations affect the C-terminal nuclear localization signal, resulting in cytosolic mislocalization and aggregation of mutant FUS [232–234].”
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PremisecitationTbk1 haploinsufficiency impairs motor neuron autophagy and accelerates clinical phenotypes as well as the accumulation of mutant SOD1 in transgenic ALS mouse models.
“Tbk1 haploinsufficiency impairs motor neuron autophagy and accelerates clinical phenotypes as well as the accumulation of mutant SOD1 in transgenic ALS mouse models [214,215].”
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PremisecitationUBQLN2 modulates MTORC1 activity, lysosomal acidification, and autophagosome maturation.
“UBQLN2 modulates MTORC1 activity, lysosomal acidification, and, in turn, autophagosome maturation [229–231].”
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PremisecitationOverexpression of ALS-linked UBQLN2 mutants triggers intracellular inclusions and motor defects in vitro and in vivo.
“while also triggering intracellular inclusions [226,227] and motor defects in vitro and in vivo [226].”
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PremisecitationUBQLN2 is an adaptor protein that binds polyubiquitinated substrates via a C-terminal UBA domain and directs them to the UPS for degradation through an N-terminal UBL domain.
“UBQLN2 (ubiquilin 2) is an adaptor protein that binds polyubiquitinated substrates via a C-terminal ubiquitin-associated (UBA) domain, and directs them to the UPS for degradation through an N-terminal ubiquitin-like (UBL) domain [218].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [218] Walters KJ, 2004, Biochim Biophys Acta source
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PremisecitationIn rats, overexpression of ALS mutant UBQLN2 leads to motor neuron loss and accumulation of autophagy substrates such as SQSTM1 and LC3-II.
“In rats, overexpression of ALS mutant UBQLN2 leads to motor neuron loss and accumulation of autophagy substrates such as SQSTM1 and LC3-II [228].”
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PremisecitationOPTN regulates vesicular trafficking, maintenance of the Golgi, NFKB/NF-κB signaling, and immune response.
“OPTN has emerged as a key player in the regulation of various cellular mechanisms, including vesicular trafficking, maintenance of the Golgi, NFKB/NF-κB signaling and immune response [253].”
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PremisecitationTransgenic mice expressing mutant CHMP2B develop progressive neurological defects, axonal pathology, early mortality, and neuronal loss reminiscent of FTD.
“Transgenic mice expressing mutant CHMP2B develop progressive neurological defects, axonal pathology, early mortality and neuronal loss reminiscent of FTD [270,271].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [270] Clayton EL, 2017, Hum Mol Genet
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- cites [271] source
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PremisecitationOverexpression of CHMP2B mutants leads to the formation of large cytoplasmic vacuoles and increased LC3-II protein levels.
“overexpression of CHMP2B mutants leads to the formation of large cytoplasmic vacuoles and increased LC3-II protein levels [266]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [266] Cox LE, 2010, PLoS One source
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PremisecitationThese mice also develop lysosomal storage pathology characterized by large neuronal aggregates derived from the endosomal system, and early microglial proliferation leading to a pro-inflammatory phenotype at later stages.
“These mice also develop lysosomal storage pathology characterized by large neuronal aggregates derived from the endosomal system [272], and early microglial proliferation leading to a pro-inflammatory phenotype at later stages [270].”
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- cites [270] Clayton EL, 2017, Hum Mol Genet
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PremisecitationIn IBMPFD murine muscle lysates, VCP mutations disrupt autophagosome maturation and fusion with lysosomes, but not the formation of early autophagosome precursors.
“In IBMPFD murine muscle lysates, VCP mutations disrupt autophagosome maturation and fusion with lysosomes, but not the formation of early autophagosome precursors [246,249].”
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PremisecitationMotor neurons from CHMP2B mutant ALS patients show increased calcium concentrations, reduced ATP availability, downregulation of the MAPK/p38 signaling pathway, and impaired autophagy initiation.
“Motor neurons from CHMP2B mutant ALS patients show increased calcium concentrations, reduced ATP availability, downregulation of the MAPK/p38 signaling pathway and impaired autophagy initiation [266].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [266] Cox LE, 2010, PLoS One source
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PremisecitationGenetic analyses have uncovered more than 20 OPTN mutations in ALS patient cohorts, accounting for approximately 3% of familial disease and approximately 1% of sporadic disease.
“Genetic analyses have uncovered >20 OPTN mutations in ALS patient cohorts, accounting for ~3% of familial disease and ~1% of sporadic disease [258].”
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PremisecitationESCRT-III is one of the four multiprotein complexes required for multivesicular body formation and is responsible for membrane deformation that enables autophagosome initiation and endolysosomal trafficking.
“ESCRT-III is one of the four multiprotein complexes required for multivesicular body formation, and is responsible for the membrane deformation that enables autophagosome initiation and endolysosomal trafficking [263].”
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PremisecitationMotor neurons and astrocytes derived from iPSCs carrying pathogenic VCP mutations demonstrate cytoplasmic TARDBP accumulation, ER stress, mitochondrial dysfunction, and oxidative stress, ultimately leading to cell death.
“Motor neurons and astrocytes derived from iPSCs carrying pathogenic VCP mutations demonstrate cytoplasmic TARDBP accumulation, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and oxidative stress, ultimately leading to cell death [252].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [252] Hall CE, 2017, Cell Rep source
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PremisecitationSQSTM1-positive inclusions are also ubiquitin-positive, consistent with a disruption in the UPS.
“SQSTM1-positive inclusions are also ubiquitin-positive, consistent with a disruption in the UPS [118].”
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PremisecitationAlthough TARDBP is typically absent from neuronal inclusions in CHMP2B-associated disease, SQSTM1-positive oligodendroglial inclusions are found in the motor cortex of ALS patients with CHMP2B mutations.
“Although TARDBP is typically absent from neuronal inclusions found in CHMP2B-associated disease, SQSTM1-positive oligodendroglial inclusions are found in the motor cortex of ALS patients with CHMP2B mutations [267].”
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PremisecitationUpon mitochondrial damage, OPTN translocates to the surface of mitochondria, an interaction stabilized via TBK1-mediated phosphorylation, facilitating engulfment of mitochondria into phagophores.
“Upon mitochondrial damage, OPTN translocates to the surface of mitochondria, an interaction that is stabilized via TBK1-mediated phosphorylation, facilitating the engulfment of mitochondria into phagophores [256].”
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PremisecitationOPTN is an autophagy receptor that binds ubiquitinated cargo via its UBAN domain and LC3 via its LIR domain, although it can also act independently of target ubiquitination.
“OPTN is an autophagy receptor that binds ubiquitinated cargo (via its UBAN domain) and LC3 (via its LIR domain) [194,254,255], although it can also act independently of target ubiquitination [254].”
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PremisecitationThe majority of pathogenic OPTN mutations are located in its UBAN domain and may impair ubiquitin binding.
“the majority of pathogenic OPTN mutations are located in its UBAN domain and may impair ubiquitin binding [259]”
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PremisecitationCHMP2B downregulation or expression of disease-associated CHMP2B mutants in Drosophila and mammalian cell lines results in aberrant endosomal structures, impaired autophagosome maturation, and cytosolic TARDBP aggregates.
“CHMP2B downregulation or expression of disease-associated CHMP2B mutants in Drosophila and mammalian cell lines results in aberrant endosomal structures, impaired autophagosome maturation, and cytosolic TARDBP aggregates [264,265,268,269].”
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PremisecitationVCP mutations are responsible for approximately 1-2% of familial ALS cases.
“but are also responsible for ~1-2% of familial ALS cases [241–243].”
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InterpretationreasoningThere is a conserved pattern of autophagy dysfunction in association with VCP mutations, implying a crucial role for VCP in autophagy and the maintenance of protein homeostasis.
“Together, these observations suggest a conserved pattern of autophagy dysfunction in association with VCP mutations, implying a crucial role for VCP in autophagy and the maintenance of protein homeostasis.”
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PremisecitationMutations in TARDBP are the third most common cause of familial autosomal dominant ALS and account for rare cases of sporadic ALS.
“Mutations in TARDBP, which encodes the transactive response DNA binding protein 43 kDa (TDP-43), are the third most common cause of familial autosomal dominant ALS and account for rare cases of sporadic ALS [290–293].”
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InterpretationreasoningCorrecting autophagy dysregulation or promoting the autophagic degradation of TARDBP may be of therapeutic benefit in ALS.
“suggest that correcting autophagy dysregulation or promoting the autophagic degradation of TARDBP may be of therapeutic benefit in ALS.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationAntagonizing the unfolded protein response through deletion of XBP1 triggers autophagy and the clearance of SOD1 inclusions, delaying disease onset and improving survival.
“antagonizing the unfolded protein response (UPR) through deletion of XBP1 [335] triggers autophagy and the clearance of SOD1 inclusions, in the process delaying disease onset and improving survival.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [335] source
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PremisecitationOverexpression of TFEB enhances LC3 expression and prevents cytotoxicity in SOD1G93A-expressing NSC-34 cells.
“overexpression of TFEB enhances LC3 expression and prevents cytotoxicity in SOD1G93A-expressing NSC-34 cells [362].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [362] Chen Y, 2015, Am J Transl Res
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PremisecitationInducing autophagy using benzoxazine compounds including 10-NCP enhances TARDBPM337V degradation and extends survival in rodent and human neurons.
“inducing autophagy using novel compounds belonging to the benzoxazine class of molecules, including 10-NCP, enhance TARDBPM337V degradation and extend survival in rodent and human neurons [357].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [357] source
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PremisecitationIbudilast induces autophagy by promoting TFEB activity, which enhances clearance of TARDBP aggregates and reduces cytotoxicity.
“the phosphodiesterase inhibitor ibudilast induces autophagy by promoting TFEB activity, which enhances clearance of TARDBP aggregates and reduces cytotoxicity [360].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [360] source
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PremisecitationMutations in SOD1 represent the second most common cause of familial ALS in Europeans and the most common cause in those of Asian descent.
“Mutations in the SOD1 gene, which encode the free radical/reactive oxygen species scavenger superoxide dismutase 1 [294,295], represent the second most common cause of familial ALS in Europeans and the most common cause in those of Asian descent [296].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [296] source
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PremisecitationEmbryonic stem cell-derived motor neurons expressing TARDBPN390D show increased levels of the autophagy suppressor BCL2 and reduced autophagic activity.
“embryonic stem cell-derived motor neurons expressing TARDBPN390D show increased levels of the autophagy suppressor, BCL2, and reduced autophagic activity [300].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [300] Huang SL, 2020, Acta Neuropathol Commun source
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InterpretationcitationHSP90AA1 and CDC37 are key suppressors of autophagy and may accentuate TARDBP-related toxicity in ALS.
“suggesting that these chaperones are key suppressors of autophagy and may accentuate TARDBP-related toxicity in ALS [354].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [354] source
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PremisecitationTARDBP downregulation promotes TFEB nuclear localization and TFEB target gene expression, but also reduces DCTN1 expression, thereby blocking autolysosome formation and impairing autophagic flux.
“TARDBP downregulation promotes TFEB nuclear localization and TFEB target gene expression, but it also reduces DCTN1 (dynactin subunit 1) expression, thereby blocking autolysosome formation and impairing autophagic flux [350].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [350] source
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PremisecitationConditional deletion of Atg7 in mouse motor neurons accentuates early ALS pathology but mitigates glial inflammation and early death.
“conditional deletion of Atg7 in mouse motor neurons accentuates early ALS pathology but mitigates glial inflammation and early death [336].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [336] source
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PremisecitationAutophagy helps eliminate synapses during development.
“autophagy helps eliminate synapses during development [377,378]”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationNewly-formed autophagosomes in neuronal processes undergo retrograde transport to the soma and proximal segments of neurites to fuse with somatodendritic lysosomes for cargo degradation, with maturation and acidification of the autophagosomal lumen developing en passant.
“Newly-formed autophagosomes in neuronal processes undergo retrograde transport to the soma and proximal segments of neurites to fuse with somatodendritic lysosomes for cargo degradation, with maturation and acidification of the autophagosomal lumen developing en passant [370,372,374].”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationBaseline autophagy in neurons constitutively operates at a highly processive level, such that maturing autophagosomes are rapidly incorporated into autolysosomes, which represent the majority of the autophagic vesicle population after autophagy induction or flux inhibition.
“Baseline autophagy in neurons constitutively operates at a highly processive level, such that maturing autophagosomes are rapidly incorporated into autolysosomes, which represent the majority of the autophagic vesicle population after autophagy induction or flux inhibition [379].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [379] source
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PremisecitationAxonal autophagy is dependent on specialized enzymatic apparatuses, including the PINK1-PRKN complex for localized mitophagy, KIF1A/UNC-104 for autophagosome formation at the synapse, and the HTT-HAP1 complex and MAPK8IP1/JIP1 for retrograde transport of autophagosomes.
“Axonal autophagy is dependent on specialized enzymatic apparatuses, including the PINK1-PRKN complex for localized mitophagy [24], KIF1A/UNC-104 for autophagosome formation at the synapse [22,25], and the HTT-HAP1 complex and MAPK8IP1/JIP1 for retrograde transport of autophagosomes [23,26].”
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PremisecitationBasal autophagy in neurons is essential for maintaining long-term neuronal health, since disruption of baseline autophagic activity in vivo causes neurodegeneration and the accumulation of inclusions containing polyubiquitinated proteins.
“Basal autophagy in neurons is essential for maintaining long-term neuronal health, since disruption of baseline autophagic activity in vivo causes neurodegeneration and the accumulation of inclusions containing polyubiquitinated proteins [380,381].”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationOPTN mutations produce microglial activation and glaucoma.
“OPTN mutations produce microglial activation and glaucoma [288]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [288] source
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Interpretationnone givenThe interplay between autophagy and TARDBP or SOD1 mutations is complex and influences ALS pathogenesis within and between different cell types of the nervous system.
“The interplay between autophagy and TARDBP or SOD1 mutations is complex and influences ALS pathogenesis within and between different cell types of the nervous system.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationSelective MTORC1 inhibition via everolimus or modulation of MTOR- and AKT-independent pathways with 10-NCP are more successful in neurons.
“Alternative methods have proven more successful in neurons, however, including selective MTORC1 inhibition via everolimus [385–387], or modulation of MTOR- and AKT-independent pathways with 10-NCP, an N10-substituted derivative of the heterocyclic dye compound and antipsychotic analog phenoxazine [384].”
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PremisecitationWith increasing age, basal autophagy and the capacity for efficient autophagosome maturation progressively deteriorate in neurons, leading to accumulation of malformed and immature autophagic vesicles, implying reduced proteostatic reserve over time.
“With increasing age, basal autophagy and the capacity for efficient autophagosome maturation progressively deteriorate in neurons, leading to accumulation of malformed and immature autophagic vesicles, implying reduced proteostatic reserve over time [382].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [382] source
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PremisecitationRapamycin and related MTOR inhibitors, as well as AKT inhibitors, are ineffective inducers of neuronal autophagy.
“rapamycin and related MTOR inhibitors, as well as AKT inhibitors, are ineffective inducers of neuronal autophagy [338,384].”
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PremisecitationC9orf72 deficiency leads to lymphocytic inflammation, lymphadenopathy, and splenomegaly.
“C9orf72 deficiency leads to lymphocytic inflammation, lymphadenopathy, and splenomegaly [149]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [149] source
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PremisecitationIn the setting of the SOD1G93A mutation, loss of TBK1 or pathogenic TBK1 mutations accentuate several pathologic features of ALS (disease onset, muscle denervation) while ameliorating others (inflammation, early death).
“in the setting of the SOD1G93A mutation, loss of TBK1 or pathogenic TBK1 mutations accentuate several pathologic features of ALS (disease onset, muscle denervation) while ameliorating others (inflammation, early death) [214].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [214] source
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PremisecitationMitochondrial compromise and ATP synthase inhibition with oligomycin A stimulate autophagy to a greater extent in astrocytes than in neurons, although both cell types activate autophagy to similar extents in the face of ischemia.
“Mitochondrial compromise and ATP synthase inhibition with oligomycin A stimulate autophagy to a greater extent in astrocytes than in neurons, although both cell types activate autophagy to similar extents in the face of ischemia [400].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [400] source
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PremisecitationActivation of microglia through genetic, infectious, inflammatory, or physical stimuli leads to stereotypical changes in their morphology, accompanied by proliferation, migration, and the release of proinflammatory cytokines and chemokines.
“Activation of microglia through genetic, infectious, inflammatory, or physical stimuli, leads to stereotypical changes in their morphology, accompanied by proliferation, migration, and the release of proinflammatory cytokines and chemokines [417–419].”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationMicroglia are macrophage-like cells that comprise 10-15% of the CNS and mediate diverse functions ranging from innate immunity and phagocytosis to synaptic pruning and the regulation of synaptic activity.
“Microglia are macrophage-like cells that comprise 10–15% of the CNS, and mediate diverse functions ranging from innate immunity and phagocytosis to synaptic pruning and the regulation of synaptic activity [416,417].”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAutophagy and phagocytosis share key morphological and mechanistic features.
“Autophagy and phagocytosis share key morphological and mechanistic features [428].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [428] source
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InterpretationcitationDifferences in autophagy between neurons and astrocytes may be due to enhanced phosphorylation of astrocytic SPHK1/SK1 with starvation, whereas benzoxazines activate neuronal but not astrocytic SPHK1 to induce autophagy.
“These differences in autophagy may be due to enhanced phosphorylation of astrocytic SPHK1/SK1 (sphingosine kinase 1) with starvation, whereas benzoxazines activate neuronal (but not astrocytic) SPHK1 to induce autophagy [11].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [11] source
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PremisecitationIn reactive gliosis, intact mitochondrial health is essential and is maintained through autophagy, such that astrocyte-specific deletion of Atg7 perturbs the balance of mitochondrial dynamics to favor fission over fusion and thereby reduces oxidative capacity.
“In reactive gliosis, a process unique to astrocytes, intact mitochondrial health is essential and is maintained through autophagy, such that astrocyte-specific deletion of Atg7 perturbs the balance of mitochondrial dynamics to favor fission over fusion and thereby reduces oxidative capacity [401].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [401] source
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PremisecitationBoth autophagy and phagocytosis rely on vesicular structures to deliver contents to lysosomes for degradation.
“For instance, both pathways rely on vesicular structures to deliver contents to lysosomes for degradation.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [428] source
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PremisecitationAutophagy is responsible for degrading HTT in astrocytes and promotes glutamate transporter expression in these cells.
“not only is autophagy responsible for degrading HTT in astrocytes, but it also promotes glutamate transporter expression in these cells [413]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [413] source
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InterpretationreasoningAstrocytes are both necessary and sufficient for neurodegeneration in this ALS model.
“implying that astrocytes are both necessary and sufficient for neurodegeneration in this ALS model.”
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PremisecitationBenzoxazines are sufficient to reduce TARDBPM337V-associated toxicity in iPSC-derived astrocytes, presumably through autophagy upregulation.
“these compounds are sufficient to reduce TARDBPM337V-associated toxicity in iPSC-derived astrocytes [357], presumably through autophagy upregulation.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [357] source
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PremisecitationIn transgenic mice overexpressing mutant SOD1 associated with ALS, astrocytes display more SOD1-positive inclusions than do neurons, and at an earlier stage.
“In transgenic mice overexpressing mutant SOD1 associated with ALS, astrocytes display more SOD1-positive inclusions than do neurons, and at an earlier stage [414].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [414] source
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PremisecitationConditional oligodendrocyte-specific deletion of Atg5 in mice leads to incomplete differentiation, reduced myelination, abnormal myelin compaction, oligodendrocytic death, and shortened life span.
“Conditional oligodendrocyte-specific deletion of Atg5 in mice leads to incomplete differentiation, reduced myelination, abnormal myelin compaction, oligodendrocytic death, and shortened life span [444].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [444] Bankston AN, 2019, Glia source
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PremisecitationC9orf72-deficient mice display lysosomal accumulation and a hyperactive immune response characterized by enhanced production of IL1B and IL6.
“C9orf72-deficient mice display lysosomal accumulation and a hyperactive immune response characterized by enhanced production of IL1B and IL6 [184,185,187,439],”
Quote in the paperSubstantial claim0 of 4 sources checkedMay combine two claims.
PremisecitationDuring OPC differentiation, autophagy becomes most active in distal OPC processes, and autophagosomes are trafficked proximally to the soma in a manner similar to neurons.
“During oligodendroglial precursor (OPC) differentiation, autophagy becomes most active in distal OPC processes, and autophagosomes are trafficked proximally to the soma in a manner similar to neurons [444].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [444] Bankston AN, 2019, Glia source
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PremisecitationAutophagy activation enhances oligodendrocyte survival and promotes myelination in a rat model of demyelinating disease.
“Consistent with these findings, autophagy activation enhances oligodendrocyte survival and promotes myelination in a rat model of demyelinating disease [448].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [448] source
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InterpretationreasoningThese findings reinforce the convergence between inflammation and autophagy in microglia and their importance for ALS pathogenesis.
“Collectively, these findings reinforce the convergence between inflammation and autophagy in microglia, and their importance for ALS pathogenesis.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationConditional Atg7 deletion in mouse Schwann cells leads to cytoplasmic swelling, ribosomal accumulation, dysmorphic ER, and dysmyelination.
“and conditional Atg7 deletion in mouse Schwann cells leads to cytoplasmic swelling, ribosomal accumulation, dysmorphic ER, and dysmyelination [459].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [459] source
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PremisecitationRapamycin fails to enhance recovery after spinal cord contusion in mice despite effective stimulation of autophagy in oligodendrocytes.
“but rapamycin fails to enhance recovery [449] despite effective stimulation of autophagy in these cells [449–451].”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationSuppression of autophagy with NTF3 disinhibits oligodendrocyte proliferation and promotes motor recovery in a separate model of spinal cord contusion.
“Paradoxically, suppression of autophagy with NTF3 (neurotrophin 3) disinhibits oligodendrocyte proliferation and promotes motor recovery in a separate model of spinal cord contusion [452].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [452] source
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PremisecitationOligodendrocyte autophagy, OPC differentiation, and myelination during development are all regulated by MTOR.
“In addition, oligodendrocyte autophagy, OPC differentiation, and myelination during development are all regulated by MTOR [445–447].”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationSchwann cell-specific PTEN deletion or EGFR overexpression attenuate peripheral nerve autophagy and lead to disorganization of the nascent neuromuscular junction.
“Additional non-cell autonomous effects are observed with Schwann cell-specific PTEN deletion or EGFR overexpression, which attenuate peripheral nerve autophagy and lead to disorganization of the nascent neuromuscular junction [461].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [461] Zhang SJ, 2019, Biochem Biophys Res Commun source
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PremisecitationCentronuclear myopathy is caused by mutations in the genes encoding MTM1 or MTMR14/Jumpy.
“For instance, centronuclear myopathy is caused by mutations in the genes encoding MTM1 (myotubularin1) or MTMR14/Jumpy (myotubularin related protein 14) [17,20].”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe positive effect of exercise on autophagy was first noted in 1984, with the observation of autophagosome accumulation after exercise in rat skeletal muscle.
“The positive effect of exercise on autophagy was first noted in 1984, with the observation of autophagosome accumulation after exercise in rat skeletal muscle [482].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [482] source
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PremisecitationNeurogenic atrophy can be partially mitigated by adrenergic stimulation, which activates autophagy through Atg7 and counteracts denervation-induced inhibition of autophagic flux.
“neurogenic atrophy can be partially mitigated by adrenergic stimulation, which activates autophagy through Atg7 and counteracts denervation-induced inhibition of autophagic flux [474].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [474] source
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PremisecitationStarvation-related atrophy is associated with upregulated autophagy, which is controlled by FOXO3 and is independent of MTOR activity.
“Starvation-related atrophy is also associated with upregulated autophagy, which in turn is controlled by the transcription factor FOXO3 and is independent of MTOR activity [473].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [473] source
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PremisecitationStimulating Schwann cell autophagy with rapamycin promotes myelination and improves peripheral nerve regeneration.
“Conversely, stimulating Schwann cell autophagy with rapamycin promotes myelination and improves peripheral nerve regeneration [465,466].”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
InterpretationreasoningAutophagy is required for muscle maintenance and homeostasis, but there is a limit or threshold beyond which autophagy stimulation may exacerbate fiber atrophy.
“The discrepancies suggested by these paradoxical findings may indicate that autophagy is required for muscle maintenance and homeostasis, but there is a limit or threshold beyond which autophagy stimulation may exacerbate fiber atrophy.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationConditional deletion of Pik3c3 in murine Schwann cells results in hypomyelination and non-cell autonomous disruption of neuronal autophagic flux and dysregulated neuronal trafficking of ERBB2 or ERBB3 receptor tyrosine kinases.
“Furthermore, conditional deletion of Pik3c3 in murine Schwann cells not only results in hypomyelination, but also in non-cell autonomous disruption of neuronal autophagic flux and dysregulated neuronal trafficking of ERBB2 or ERBB3 receptor tyrosine kinases [460].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [460] source
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PremisecitationIn ALS, skeletal muscle-specific expression of SOD1G93A is associated with atrophy and elevated autophagy.
“In ALS, skeletal muscle-specific expression of SOD1G93A is associated with atrophy and elevated autophagy [479],”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [479] source
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PremisecitationSimilar effects have been seen in humans and mice after strenuous exercise, interpreted as a response to exercise-related muscle breakdown.
“Similar effects have been seen in humans and mice after strenuous exercise, interpreted as a response to exercise-related muscle breakdown [482,483].”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
InterpretationreasoningDiscrepant results may be due to effects of genetic background unique to each disease, resulting in excessive autophagy stimulation in centronuclear myopathy but insufficient autophagy in DMD.
“These discrepant results may be due to effects of the genetic background unique to each disease, resulting in excessive autophagy stimulation in centronuclear myopathy, but insufficient autophagy in DMD.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationLoss-of-function mutations in MTM1 or MTMR14 prevent these enzymes from metabolizing phosphoinositides required for autophagy, thereby disinhibiting autophagy flux and muscle atrophy.
“These loss-of-function mutations prevent these enzymes from metabolizing phosphoinositides required for autophagy, thereby disinhibiting autophagy flux and muscle atrophy [17,20].”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationGenetic ablation of RUNX1 disinhibits autophagy and worsens atrophy.
“Conversely, genetic ablation of RUNX1 disinhibits autophagy and worsens atrophy [472].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [472] source
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PremisecitationConditional Atg7 deletion in mouse skeletal muscle leads to atrophy, weakness, and accumulation of unhealthy mitochondria and sarcoplasmic reticulum.
“and conditional Atg7 deletion in mouse skeletal muscle leads to atrophy, weakness, and accumulation of unhealthy mitochondria and sarcoplasmic reticulum [477].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [477] source
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PremisecitationSkeletal muscle denervation causes neurogenic atrophy and may activate autophagy.
“skeletal muscle denervation causes neurogenic atrophy and may activate autophagy;”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [472] source
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PremisecitationAged rats show elevated basal mitophagy, higher levels of mitophagy proteins, higher TFEB expression and lysosomal markers than young mice.
“Aged rats also show elevated basal mitophagy, higher levels of mitophagy proteins, higher TFEB expression and lysosomal markers than young mice;”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [497] source
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PremisecitationSarcopenia involves autophagy of muscle structural components, and attenuation of autophagy with PPARGC1A overexpression mitigates sarcopenia.
“On the other hand, sarcopenia involves autophagy of muscle structural components, and attenuation of autophagy with PPARGC1A overexpression mitigates sarcopenia [495].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [495] source
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InterpretationreasoningThese negative trials, together with lithium's narrow therapeutic index, severely limit the therapeutic utility of lithium for ALS.
“These negative trials, together with lithium’s narrow therapeutic index, severely limit the therapeutic utility of lithium for ALS (Figure 3).”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningUse of rapamycin in ALS is complicated by its potential for insufficient induction of neuronal autophagy and its capacity for modulating multiple MTOR-dependent downstream pathways.
“but the use of rapamycin in ALS is complicated not only by its potential for insufficient induction of neuronal autophagy per se, but also its capacity for modulating multiple MTOR-dependent downstream pathways (Figure 3).”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationMouse muscle shows age-related decline in autophagy machinery (LC3, BECN1, and LAMP2), and these deficiencies are partially mitigated by 8 weeks of treadmill exercise.
“Mouse muscle also shows age-related decline in autophagy machinery (LC3, BECN1, and LAMP2), and these deficiencies are partially mitigated by 8 weeks of treadmill exercise [491].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [491] source
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PremisecitationDespite early enthusiasm over lithium in patients and mouse models, five subsequent trials showed no clinical benefit in survival or neuromuscular outcomes for ALS patients.
“Despite early enthusiasm over lithium in patients and mouse models [505,506], five subsequent trials showed no clinical benefit in survival or neuromuscular outcomes for ALS patients [507–511].”
Quote in the paperSubstantial claim0 of 7 sources checked- cites [505] source
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- cites [506] source
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- cites [508] source
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- cites [509] source
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- cites [510] source
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- cites [511] source
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Interpretationnone givenTreatment with autophagy modulating drugs runs the risk of incurring intolerable side effects and toxicities, especially when given on a long-term basis.
“Additionally, treatment with autophagy modulating drugs runs the risk of incurring intolerable side effects and toxicities, especially when given on a long-term basis that may be required to prevent or delay late-onset neurodegenerative diseases.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationSkeletal muscle autophagy declines with aging in Drosophila and can be rescued by FOXO overexpression or constitutive activation of EIF4EBP1.
“On the one hand, skeletal muscle autophagy declines with aging in Drosophila and can be rescued by FOXO overexpression or constitutive activation of EIF4EBP1 [490].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [490] source
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PremisecitationNeither amino acid starvation-induced autophagy nor amino acid provision-induced RPS6KB phosphorylation is affected by rapamycin, suggesting that MTOR is dispensable for this pathway.
“Neither event is affected by rapamycin, suggesting that MTOR is dispensable for this pathway [512].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [512] source
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Probably not a substantial claim: may not pass S2 (checkable).
InterpretationreasoningThe effectiveness of autophagy inducers must be tested rigorously in model systems that do not depend upon overexpression of disease-associated proteins, since this approach may inappropriately emphasize strategies that reduce non-physiological accumulation of exogenous proteins.
“Fourth, the effectiveness of these compounds must be tested rigorously in model systems that do not depend upon the overexpression of disease-associated proteins, since this approach may inappropriately emphasize strategies that reduce the non-physiological accumulation of exogenous proteins.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationDrawbacks of chronic rapamycin therapy include cytopenias, nephrotoxicity, metabolic syndrome, dermatitis, and pneumonitis.
“the drawbacks of chronic rapamcyin therapy – including cytopenias, nephrotoxicity, metabolic syndrome, dermatitis, and pneumonitis [502,503] – are well known.”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationAmino acid starvation induces autophagy, whereas amino acid provision results in RPS6KB/p70S6K phosphorylation and autophagy suppression.
“amino acid starvation induces autophagy, whereas amino acid provision results in RPS6KB/p70S6K phosphorylation and autophagy suppression [512].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [512] source
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PremisecitationRapamycin has been extensively utilized for transplant rejection prophylaxis and graft-versus-host disease, as well as seizure control and reduction of tumors in tuberous sclerosis complex patients.
“Rapamycin has been extensively utilized for transplant rejection prophylaxis and graft-versus-host disease, as well as seizure control and reduction of tumors in tuberous sclerosis complex patients [499–501].”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S4 (based). May combine two claims.
Premisenone givenLithium has numerous multi-target effects, including depletion of IP3 through IMPase, activating nitric oxide synthase, inhibiting GSK3B, stimulating NMDA receptors and enhancing glutamatergic tone.
“Similarly, lithium has numerous multi-target effects, including depletion of IP3 through IMPase, activating nitric oxide synthase, inhibiting GSK3B, stimulating NMDA receptors and enhancing glutamatergic tone, among many others (middle).”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningLithium has a narrow therapeutic index, potentially explaining its apparent lack of neuroprotective effects in human trials for neurodegenerative disease to date.
“This results in a narrow therapeutic index for lithium, potentially explaining its apparent lack of neuroprotective effects in human trials for neurodegenerative disease to date.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationAutophagy induction is seen with acute bouts of exercise, and this short-term increase appears to require PPARGC1A.
“Autophagy induction is not only seen with endurance exercise, but also acute bouts of exercise, and this short-term increase in autophagy appears to require PPARGC1A [488].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [488] source
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PremisecitationIn aged rats, these changes are accompanied by reduced adaptive reserve in response to denervation, with impaired autophagy induction and lower levels of mitophagy compared to young rats.
“These changes are accompanied by reduced adaptive reserve in response to denervation, with impaired autophagy induction and lower levels of mitophagy compared to young rats [496].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [496] source
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PremisecitationIn aged rats, muscle tissues display elevated basal levels of proteolysis, higher expression of autophagy proteins and accumulation of unfolded protein response elements.
“In aged rats, muscle tissues display elevated basal levels of proteolysis, higher expression of autophagy proteins and the accumulation of unfolded protein response elements.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [496] source
Not checked in the free run.
May combine two claims.
PremisecitationMTOR-independent methods for stimulating autophagy include direct stimulation of AKT and BECN1, activating MAPK8/JNK1 to dissociate BCL2 from BECN1, applying Tat-Beclin 1, SIRT1-associated starvation, and disrupting nonsense-mediated RNA decay.
“The array of MTOR-independent methods for stimulating autophagy also includes direct stimulation of AKT and BECN1, activating MAPK8/JNK1 to dissociate BCL2 from (and thereby disinhibit) BECN1, applying the synthetic peptide Tat-Beclin 1, SIRT1-associated starvation, and disrupting nonsense-mediated RNA decay [513–517] (Figure 3).”
Quote in the paperNot a substantial claim0 of 5 sources checkedProbably not a substantial claim: may not pass S4 (based).
Interpretationnone givenCell and animal models may not faithfully reproduce autophagy regulation in healthy subjects or humans with disease.
“For instance, cell and animal models may not faithfully reproduce autophagy regulation in healthy subjects or humans with disease.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationAging is associated with a decline in muscle mass (sarcopenia) and mitochondrial function, both of which are associated with dysregulated autophagy.
“Aging is associated with a decline in muscle mass (termed sarcopenia) and mitochondrial function, both of which are associated with dysregulated autophagy [489].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [489] source
Not checked in the free run.
May combine two claims.
PremisecitationSkeletal muscle from aged rats exhibits lower LC3 expression, suggesting reduced basal autophagy and an overall decreased capacity for autophagy.
“Supporting this, skeletal muscle from aged rats exhibits lower LC3 expression, suggesting reduced levels of basal autophagy and an overall decreased capacity for autophagy [494].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [494] source
Not checked in the free run.
The paper relies on this without support.
Findings from animal and cell models of ALS (e.g., mouse, zebrafish, iPSC) are relevant to human ALS pathogenesis.
“These results are consistent with those in animal models, suggesting that the endogenously encoded C9orf72 repeat expansion mutation leads to toxicity by both gain and loss of function mechanisms.”
The authors state this as an assumption.
c9orf72 knockout in mouse models the loss of function attributed to the C9orf72 hexanucleotide repeat expansion.
“Paradoxically, however, c9orf72 knockout in mouse (which models the loss of function attributed to the hexanucleotide repeat expansion) enhances autophagy by de-repressing MTOR and, in turn, increasing TFEB nuclear translocation [179,180].”
The paper relies on this without support.
Autophagy-based therapies can be effective for ALS and related neurodegenerative diseases.
“This review thereby provides a framework not only to guide further investigations of neuronal autophagy but also to refine therapeutic strategies for ALS and related neurodegenerative diseases.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Autophagy maintains cellular and organismal integrity by breaking down cellular components and organelles for reuse or redistribution.
“This self-consumptive pathway maintains cellular and organismal integrity in to the context of various developmental events or stressors by breaking down cellular components and organelles for reuse or redistribution.”
From Modulation of the gut–brain axis via the gut microbiota: a new era in treatment of amyotrophic lateral sclerosis (2023) · cites this paper as [85]
Autophagy and proteostasis are observed in experimental models of fALS and may play a key role in the pathogenesis of sALS.
“Chua et al. (85) have shown that autophagy and proteostasis are not only observed in experimental models of fALS, where specific genetic mutations can impair autophagic effectors or generate proteotoxic stress, but may also play a key role in the pathogenesis of sALS.”
From Modulation of the gut–brain axis via the gut microbiota: a new era in treatment of amyotrophic lateral sclerosis (2023) · cites this paper as [85]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
PPARGC1A is described as both suppressing and driving muscle autophagy
MinorFigure 2 labels PPARGC1A a suppressor of muscle autophagy, while the skeletal-muscle section says its overexpression drives autophagy. The figure does not qualify the suppressive effect by context.
“In muscle, specific transcription factors can exert activating (FOXO3) or suppressive (PPARGC1A, RUNX1) effects on autophagy”
“PPARGC1A/PGC1A (PPARG coactivator 1A) overexpression drives non-MTOR-dependent autophagy by increasing TFEB nuclear localization in dystrophin-deficient muscle fibers [19]”
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BackgroundTDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis
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How to Interpret LC3 Immunoblotting
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A Gene Network Regulating Lysosomal Biogenesis and Function
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BackgroundAn Overview of Autophagy: Morphology, Mechanism, and Regulation
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BackgroundPromotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene
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BackgroundNutrient-dependent mTORC1 Association with the ULK1–Atg13–FIP200 Complex Required for Autophagy
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“lactate transporter in the CNS whose expression is regulated by autophagy [458].”
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“Mutations in VCP most commonly lead to the combined disorder of inclusion body myopathy, Paget disease of the bone, and FTD (IBMPFD) [240], but are also responsible for ~1-2% of familial ALS cases [241–243].”
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BackgroundMutations of optineurin in amyotrophic lateral sclerosis
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“~3% of familial disease and ~1% of sporadic disease [258].”
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“This notion is underscored by the fact that nearly every neurodegenerative disorder is marked by the accumulation of misfolded proteins within or adjacent to affected neurons and glia, in spite of heterogeneous clinical and pathological characteristics among these diseases [68,69].”
BackgroundExome Sequencing Reveals VCP Mutations as a Cause of Familial ALS
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Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia
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BackgroundRecurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone.
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“Despite early enthusiasm over lithium in patients and mouse models [505,506], five subsequent trials showed no clin-”
Background<i>C9orf72</i> is required for proper macrophage and microglial function in mice
O’Rourke, J. G., Bogdanik, L., Yáñez, A., Lall, D., Wolf, A. J., Muhammad, A. K. M. G., Ho, R., Carmona, S., Vit, J. P., Zarrow, J., et al. (2016) · Science · doi:10.1126/science.aaf1064 · Cited by 550 · see citing works
The Signaling Adaptor p62 Is an Important NF-κB Mediator in Tumorigenesis
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Genetic epidemiology of amyotrophic lateral sclerosis: a systematic review and meta-analysis
Zou, Z.-Y., Zhou, Z.-R., Che, C.-H., Liu, C.-Y., He, R.-L., & Huang, H.-P. (2017) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp-2016-315018 · Cited by 540 · cited 1× · see citing works
“common cause in those of Asian descent [296].”
BackgroundHetz, C., Thielen, P., Matus, S., Nassif, M., Court, F., Kiffin, R., Martinez, G., Cuervo, A. M., Brown, R. H., & Glimcher, L. H. (2009) · Genes & Development · doi:10.1101/gad.1830709 · Cited by 530 · cited 5× · see citing works
“Furthermore, antagonizing the unfolded protein response (UPR) through deletion of XBP1 [335] triggers autophagy and the clearance of SOD1 inclusions, in the process delaying disease onset and improving survival.”
BackgroundInfluentialPuertollano, R., Ferguson, S. M., Brugarolas, J., & Ballabio, A. (2018) · The EMBO Journal · doi:10.15252/embj.201798804 · Cited by 519 · see citing works
Polyubiquitin chain-induced p62 phase separation drives autophagic cargo segregation
Sun, D., Wu, R., Zheng, J., Li, P., & Yu, L. (2018) · Cell Research · doi:10.1038/s41422-018-0017-7 · Cited by 515 · cited 1× · see citing works
“The resulting complex undergoes liquid-liquid phase separation (LLPS), facilitating assembly of the phagophore [92,93].”
BackgroundSkeletal Muscle Is a Primary Target of SOD1G93A-Mediated Toxicity
Dobrowolny, G., Aucello, M., Rizzuto, E., Beccafico, S., Mammucari, C., Bonconpagni, S., Belia, S., Wannenes, F., Nicoletti, C., Del Prete, Z., et al. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.09.002 · Cited by 513 · cited 1× · see citing works
“○ Neuromuscular disease: In ALS, skeletal musclespecific expression of SOD1 is associated with atrophy and elevated autophagy [479], but these effects are mitigated by siRNA-mediated MAP1LC3B knockdown and the subsequent reduction of auto-”
BackgroundWen, X., Tan, W., Westergard, T., Krishnamurthy, K., Markandaiah, S. S., Shi, Y., Lin, S., Shneider, N. A., Monaghan, J., Pandey, U. B., et al. (2014) · Neuron · doi:10.1016/j.neuron.2014.12.010 · Cited by 513 · see citing works
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“Axonal autophagy is dependent on specialized enzymatic apparatuses, including the PINK1-PRKN complex for localized mitophagy [24], KIF1A/ UNC-104 for autophagosome formation at the synapse [22,25],”
Backgroundp62 Is a Key Regulator of Nutrient Sensing in the mTORC1 Pathway
Durán, Á., Amanchy, R., Linares, J. F., Joshi, J. P., Abu‐Baker, S., Porollo, A., Hansen, M., Moscat, J., & Díaz-Meco, M. T. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.06.038 · Cited by 502 · see citing works
Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease
Ju, J.-S., Fuentealba, R. A., Miller, S. E., Jackson, E., Piwnica-Worms, D., Baloh, R. H., & Weihl, C. C. (2009) · Journal of Cell Biology · doi:10.1083/jcb.200908115 · Cited by 494 · cited 2× · see citing works
“some maturation and fusion with lysosomes, but not the formation of early autophagosome precursors [246,249].”
BackgroundArnold, E. S., Ling, S., Huelga, S. C., Lagier‐Tourenne, C., Polymenidou, M., Ditsworth, D., Kordasiewicz, H. B., McAlonis‐Downes, M., Platoshyn, O., Parone, P. A., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1222809110 · Cited by 494 · cited 2× · see citing works
“the A315T [301,308,319], Q331K [310], M337V [301,310,311,311,320–322], G348C [308] mutations, knock-in mutant TARDBP [300], or tardbp knockouts [323–328] (these models are reviewed in further detail elsewhere [329–334]).”
BackgroundESCRT-III Dysfunction Causes Autophagosome Accumulation and Neurodegeneration
Lee, J., Beigneux, A. P., Ahmad, S. T., Young, S. G., & Gao, F. (2007) · Current Biology · doi:10.1016/j.cub.2007.07.029 · Cited by 490 · cited 1× · see citing works
“In agreement with these observations, CHMP2B downregulation or expression of disease-associated CHMP2B mutants in Drosophila and mammalian cell lines results in aberrant endosomal structures, impaired autophagosome maturation, and cytosolic TARDBP aggregates [264,265,268,269].”
ResultMori, K., Arzberger, T., Grässer, F. A., Gijselinck, I., May, S., Rentzsch, K., Weng, S., Schludi, M. H., van der Zee, J., Cruts, M., et al. (2013) · Acta Neuropathologica · doi:10.1007/s00401-013-1189-3 · Cited by 482 · see citing works
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“with the G93A [214,215,335–338], G86R [335,339], or H46R/ H48Q [340] mutations (also reviewed elsewhere [341–344]).”
BackgroundInfluentialFarg, M. A., Sundaramoorthy, V., Sultana, J. M., Yang, S., Atkinson, R. A. K., Levina, V., Halloran, M. A., Gleeson, P. A., Blair, I. P., Soo, K. Y., et al. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu068 · Cited by 478 · cited 1× · see citing works
“expressed in normal and neoplastic cells) family [143,144] and binds the GTPases RAB7 and RAB11, which are involved in endosome maturation and recycling [145].”
BackgroundAl-Sarraj, S., King, A., Troakes, C., Smith, B., Maekawa, S., Bodi, I., Rogelj, B., Al-Chalabi, A., Hortobágyi, T., & Shaw, C. E. (2011) · Acta Neuropathologica · doi:10.1007/s00401-011-0911-2 · Cited by 475 · see citing works
Biogenesis and Cargo Selectivity of Autophagosomes
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“LC3-interacting region (LIR) and separate motifs for binding polyubiquitinated proteins [41].”
BackgroundInfluentialSchwann cell autophagy, myelinophagy, initiates myelin clearance from injured nerves
Gomez-Sanchez, J. A., Carty, L., Iruarrizaga-Lejarreta, M., Palomo-Irigoyen, M., Varela-Rey, M., Griffith, M., Hantke, J., Macias-Camara, N., Azkargorta, M., Aurrekoetxea, I., et al. (2015) · Journal of Cell Biology · doi:10.1083/jcb.201503019 · Cited by 453 · cited 1× · see citing works
“somes in a process termed “myelinophagy” [459,462,463], and this function is impaired by”
BackgroundLepore, A. C., Rauck, B., Dejea, C., Pardo, A. C., Rao, M. S., Rothstein, J. D., & Maragakis, N. J. (2008) · Nature Neuroscience · doi:10.1038/nn.2210 · Cited by 441 · cited 1× · see citing works
“In addition, transplantation of wild-type astrocytes into SOD1 rat spinal cords was neuroprotective [348], and limited overexpression of NRF2 in astrocytes mitigated neurodegeneration in SOD1 and SOD1 mice [340].”
BackgroundTresse, E., Salomons, F. A., Vesa, J., Bott, L. C., Kimonis, V., Yao, T.-P., Dantuma, N. P., & Taylor, J. P. (2010) · Autophagy · doi:10.4161/auto.6.2.11014 · Cited by 437 · see citing works
The Autophagy–Lysosomal Pathway in Neurodegeneration: A TFEB Perspective
Martini-Stoica, H., Xu, Y., Ballabio, A., & Zheng, H. (2016) · Trends in Neurosciences · doi:10.1016/j.tins.2016.02.002 · Cited by 436 · see citing works
Dysregulation of the ALS-associated gene TDP-43 leads to neuronal death and degeneration in mice
Igaz, L. M., Kwong, L. K., Lee, E. B., Chen‐Plotkin, A. S., Swanson, E., Unger, T. L., Malunda, J. A., Xu, Y., Winton, M. J., Trojanowski, J. Q., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci44867 · Cited by 434 · see citing works
Autophagy induction enhances TDP43 turnover and survival in neuronal ALS models
Barmada, S. J., Serio, A., Arjun, A., Bilican, B., Daub, A., Ando, D. M., Tsvetkov, A., Pleiss, M., Li, X., Peisach, D., et al. (2014) · Nature Chemical Biology · doi:10.1038/nchembio.1563 · Cited by 431 · cited 3× · see citing works
“For example, inducing autophagy using novel compounds belonging to the benzoxazine class of molecules, including 10-NCP, enhance TARDBP degradation and extend survival in rodent and human neurons [357].”
BackgroundSelf-citationWurmser, A. E., Sato, T. K., & Emr, S. D. (2000) · The Journal of Cell Biology · doi:10.1083/jcb.151.3.551 · Cited by 425 · cited 2× · see citing works
“Fusion of the autophagosome and lysosome is mediated by the homotypic fusion and protein sorting (HOPS) complex, whose subunits include VPS11, VPS16, VPS18, VPS33A, VPS39, and VPS41 [45,46].”
BackgroundAutophagy revisited: A conversation with Christian de Duve
Klionsky, D. (2008) · Autophagy · doi:10.4161/auto.6398 · Cited by 422 · see citing works
Sellier, C., Campanari, M., Julie Corbier, C., Gaucherot, A., Kolb‐Cheynel, I., Oulad‐Abdelghani, M., Ruffenach, F., Page, A., Ciura, S., Kabashi, E., et al. (2016) · The EMBO Journal · doi:10.15252/embj.201593350 · Cited by 414 · see citing works
Self-citationDeleterious Variants of FIG4, a Phosphoinositide Phosphatase, in Patients with ALS
Chow, C. Y., Landers, J. E., Bergren, S. K., Sapp, P. C., Grant, A. E., Jones, J. M., Everett, L., Lenk, G. M., McKenna-Yasek, D. M., Weisman, L. S., et al. (2009) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2008.12.010 · Cited by 407 · cited 1× · see citing works
“Autosomal dominant FIG4 mutations are associated with rare forms of familial ALS [470], suggesting that inefficient myelinophagy may result in the loss of motor neurons and”
BackgroundThe C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy
Webster, C. P., Smith, E. F., Bauer, C. S., Moller, A., Hautbergue, G. M., Ferraiuolo, L., Myszczynska, M. A., Higginbottom, A., Walsh, M. J., Whitworth, A. J., et al. (2016) · The EMBO Journal · doi:10.15252/embj.201694401 · Cited by 404 · see citing works
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“phagy [492], together with mitochondrial fragmentation and mitochondrial fission machinery in muscle, indicate inefficient mitophagic flux in aging muscle [493].”
BackgroundFibrous and protoplasmic astrocytes are biochemically and developmentally distinct
Miller, R., & RAFF, M. C. (1984) · Journal of Neuroscience · doi:10.1523/jneurosci.04-02-00585.1984 · Cited by 396 · see citing works
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“and the HTT-HAP1 complex and MAPK8IP1/JIP1 for retrograde transport of autophagosomes [23,26].”
BackgroundAutophagy in microglia degrades extracellular β-amyloid fibrils and regulates the NLRP3 inflammasome
Cho, M.-H., Cho, K., Kang, H.-J., Jeon, E.-Y., Kim, H.-S., Kwon, H.-J., Kim, H.-M., Kim, D.-H., & Yoon, S.-Y. (2014) · Autophagy · doi:10.4161/auto.29647 · Cited by 395 · cited 2× · see citing works
“In line with these connections between phagocytosis and autophagy, microglial phagocytosis of Aβ deposits in Alzheimer disease models [430,431] requires the autophagy-related factors BECN1, ATG7 and LC3 [432,433].”
BackgroundALS phenotypes with mutations in <i>CHMP2B</i> (charged multivesicular body protein 2B)
Parkinson, N., Ince, P. G., Smith, M. O., Highley, R., Skibinski, G., Andersen, P. M., Morrison, K. E., Pall, H. S., Hardiman, O., Collinge, J., et al. (2006) · Neurology · doi:10.1212/01.wnl.0000231510.89311.8b · Cited by 395 · see citing works
Ubiquitin, cellular inclusions and their role in neurodegeneration
Alves-Rodrigues, A., Gregori, L., & Figueiredo-Pereira, M. E. (1998) · Trends in Neurosciences · doi:10.1016/s0166-2236(98)01276-4 · Cited by 393 · cited 1× · see citing works
“This notion is underscored by the fact that nearly every neurodegenerative disorder is marked by the accumulation of misfolded proteins within or adjacent to affected neurons and glia, in spite of heterogeneous clinical and pathological characteristics among these diseases [68,69].”
BackgroundEvans, A. (2013) · Oxford University Press eBooks · doi:10.1093/hesc/9780199655298.003.0002 · Cited by 381 · see citing works
Wang, I.-F., Guo, B.-S., Liu, Y.-C., Wu, C.-C., Yang, C.-H., Tsai, K.-J., & Shen, C.-K. J. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1206362109 · Cited by 377 · cited 2× · see citing works
“Inhibition of MTOR likewise reduces TARDBP aggregation and toxicity in multiple cell and animal models of ALS [353,358,359].”
BackgroundLucin, K. M., O’Brien, C. E., Bieri, G., Czirr, E., Mosher, K. I., Abbey, R. J., Mastroeni, D. F., Rogers, J., Spencer, B., Masliah, E., et al. (2013) · Neuron · doi:10.1016/j.neuron.2013.06.046 · Cited by 374 · cited 2× · see citing works
“In line with these connections between phagocytosis and autophagy, microglial phagocytosis of Aβ deposits in Alzheimer disease models [430,431] requires the autophagy-related factors BECN1, ATG7 and LC3 [432,433].”
Background<i>TDP</i> ‐ <i>43</i> mutation in familial amyotrophic lateral sclerosis
Yokoseki, A., Shiga, A., Tan, C., Tagawa, A., Kaneko, H., Koyama, A., Eguchi, H., Tsujino, A., Ikeuchi, T., Kakita, A., et al. (2008) · Annals of Neurology · doi:10.1002/ana.21392 · Cited by 373 · see citing works
Gong, Y. H., Parsadanian, A. S., Andreeva, A., Snider, W. D., & Elliott, J. L. (2000) · Journal of Neuroscience · doi:10.1523/jneurosci.20-02-00660.2000 · Cited by 372 · cited 2× · see citing works
“with the G93A [214,215,335–338], G86R [335,339], or H46R/ H48Q [340] mutations (also reviewed elsewhere [341–344]).”
Autophagosome Biogenesis in Primary Neurons Follows an Ordered and Spatially Regulated Pathway
Maday, S., & Holzbaur, E. L. F. (2014) · Developmental Cell · doi:10.1016/j.devcel.2014.06.001 · Cited by 372 · cited 1× · see citing works
“begins outside of the soma, in the distal axon tip [370,372,373].”
BackgroundTDP-43 Is a Developmentally Regulated Protein Essential for Early Embryonic Development
Sephton, C. F., Good, S. K., Atkin, S., Dewey, C. M., Mayer, P., Herz, J., & Yu, G. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.061846 · Cited by 370 · see citing works
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p62 filaments capture and present ubiquitinated cargos for autophagy
Zaffagnini, G., Savova, A., Danieli, A., Romanov, J., Tremel, S., Ebner, M., Peterbauer, T., Sztacho, M., Trapannone, R., Tarafder, A. K., et al. (2018) · The EMBO Journal · doi:10.15252/embj.201798308 · Cited by 361 · cited 1× · see citing works
“The resulting complex undergoes liquid-liquid phase separation (LLPS), facilitating assembly of the phagophore [92,93].”
BackgroundOxidative and endoplasmic reticulum stress interplay in sporadic amyotrophic lateral sclerosis
Ilieva, E. V., Ayala, V., Jove, M., Dalfo, E., Cacabelos, D., Povedano, M., Bellmunt, M. J., Ferrer, I., Pamplona, R., & Portero-Otin, M. (2007) · Brain · doi:10.1093/brain/awm190 · Cited by 358 · see citing works
Microglia in ALS: The Good, The Bad, and The Resting
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Microglia Function in Central Nervous System Development and Plasticity
Schafer, D. P., & Stevens, B. (2015) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a020545 · Cited by 353 · cited 1× · see citing works
“pruning and the regulation of synaptic activity [416,417].”
BackgroundRaben, N., Hill, V., Shea, L., Takikita, S., Baum, R., Mizushima, N., Ralston, E., & Plotz, P. (2008) · Human Molecular Genetics · doi:10.1093/hmg/ddn292 · Cited by 352 · cited 1× · see citing works
“skeletal muscle leads to accumulation of ubiquitinpositive inclusions and ultrastructural disorganization [478].”
BackgroundAutophagy and the ubiquitin-proteasome system: Collaborators in neuroprotection
Nedelsky, N. B., Todd, P. K., & Taylor, J. P. (2008) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2008.10.002 · Cited by 351 · cited 1× · see citing works
“● Adaptive proteostasis: Similar to neurons [397], autopha-”
BackgroundLoss of murine TDP-43 disrupts motor function and plays an essential role in embryogenesis
Kraemer, B. C., Schuck, T., Wheeler, J. M., Robinson, L. C., Trojanowski, J. Q., Lee, V. M. Y., & Schellenberg, G. D. (2010) · Acta Neuropathologica · doi:10.1007/s00401-010-0659-0 · Cited by 350 · see citing works
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“[297], but also increases the risk of death in iPSC-derived astrocytes [299].”
BackgroundSelf-citationBeck, J., Poulter, M., Hensman, D., Rohrer, J. D., Mahoney, C. J., Adamson, G., Campbell, T., Uphill, J., Borg, A., Fratta, P., et al. (2013) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2013.01.011 · Cited by 345 · see citing works
Dipeptide repeat protein pathology in C9ORF72 mutation cases: clinico-pathological correlations
Mackenzie, I. R., Arzberger, T., Kremmer, E., Troost, D., Lorenzl, S., Mori, K., Weng, S.-M., Haass, C., Kretzschmar, H. A., Edbauer, D., et al. (2013) · Acta Neuropathologica · doi:10.1007/s00401-013-1181-y · Cited by 345 · see citing works
Transcriptional and epigenetic regulation of autophagy in aging
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Ubiquitin-independent function of optineurin in autophagic clearance of protein aggregates
Korac, J., Schaeffer, V., Kovacevic, I., Clement, A. M., Jungblut, B., Behl, C., Terzic, J., & Dikic, I. (2013) · Journal of Cell Science · doi:10.1242/jcs.114926 · Cited by 336 · cited 1× · see citing works
“OPTN is an autophagy receptor that binds ubiquitinated cargo (via its UBAN domain) and LC3 (via its LIR domain) [194,254,255], although it can also act independently of target ubiquitination [254].”
BackgroundCiura, S., Lattante, S., Le Ber, I., Latouche, M., Tostivint, H., Brice, A., & Kabashi, E. (2013) · Annals of Neurology · doi:10.1002/ana.23946 · Cited by 333 · cited 1× · see citing works
“[182,183], implying that the C9orf72 protein is essential for”
BackgroundSelf-citationAutophagy and neurodegeneration
Frake, R. A., Ricketts, T., Menzies, F. M., & Rubinsztein, D. C. (2015) · Journal of Clinical Investigation · doi:10.1172/jci73944 · Cited by 332 · see citing works
Constitutive Activation of Chaperone-mediated Autophagy in Cells with Impaired Macroautophagy
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“Granulophagy can also serve a compensatory role in the setting of dysfunctional macroautophagy [67].”
BackgroundBilican, B., Serio, A., Barmada, S. J., Nishimura, A. L., Sullivan, G. J., Carrasco, M., Phatnani, H. P., Puddifoot, C. A., Story, D., Fletcher, J., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1202922109 · Cited by 328 · cited 2× · see citing works
“iPSC-derived motor neurons harboring the ALS-associated TARDBP mutation demonstrate an accumulation of insoluble mutant TARDBP at native expression levels [298], which in previous models has not only been closely linked to neurodegeneration”
BackgroundSelf-citationArginine methylation next to the PY‐NLS modulates Transportin binding and nuclear import of FUS
Dormann, D., Madl, T., Valori, C. F., Bentmann, E., Tahirovic, S., Abou‐Ajram, C., Kremmer, E., Ansorge, O., Mackenzie, I. R. A., Neumann, M., et al. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.261 · Cited by 326 · see citing works
The Role of the Selective Adaptor p62 and Ubiquitin-Like Proteins in Autophagy
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“Besides its LIR domain, SQSTM1 contains an Nterminal Phox1 and Bem1p (PB1) domain, a zinc finger (ZZ), a TRAF6 (TNF receptor associated factor 6)-binding (TB) motif, a KEAP1-interacting region (KIR), and a ubiquitin-associated (UBA) domain [85,86].”
BackgroundInfluentialLim, J., Lachenmayer, M. L., Wu, S., Liu, W., Kundu, M., Wang, R., Komatsu, M., Oh, Y. J., Zhao, Y., & Yue, Z. (2015) · PLoS Genetics · doi:10.1371/journal.pgen.1004987 · Cited by 323 · cited 1× · see citing works
“domain of SQSTM1 is phosphorylated by ULK1 on serine 407, liberating the protein from dimeric inactivation [89].”
BackgroundPLIC proteins or ubiquilins regulate autophagy‐dependent cell survival during nutrient starvation
N'Diaye, E., Kajihara, K. K., Hsieh, I., Morisaki, H., Debnath, J., & Brown, E. J. (2009) · The EMBO Reports · doi:10.1038/embor.2008.238 · Cited by 323 · cited 1× · see citing works
“UBQLN2 can also act as an autophagy receptor by directly interacting with LC3 in autophagosomes [219,220].”
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Autophagy, aging, and age-related neurodegeneration
Palmer, J. E., Wilson, N., Son, S. M., Obrocki, P., Wróbel, L., Rob, M., Takla, M., Korolchuk, V. I., & Rubinsztein, D. C. (2024) · Neuron · doi:10.1016/j.neuron.2024.09.015 · Cited by 255 · see citing works
The role of lysosomes in metabolic and autoimmune diseases
Gros, F., & Muller, S. (2023) · Nature Reviews Nephrology · doi:10.1038/s41581-023-00692-2 · Cited by 199 · see citing works
DJ-1 is an essential downstream mediator in PINK1/parkin-dependent mitophagy
Imberechts, D., Kinnart, I., Wauters, F., Terbeek, J., Manders, L., Wierda, K. D. B., Eggermont, K., Madeiro, R. F., Sue, C. M., Verfaillie, C. M., et al. (2022) · Brain · doi:10.1093/brain/awac313 · Cited by 161 · see citing works
“Mutations in the genes for optineurin and its interactor TBK1 cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia.(54) Interestingly, although most patients with PARK7 mutations have typical early-onset PD, some develop ALS and dementia in addition to parkinsonism.”
BackgroundMeng, K., Jia, H., Hou, X., Zhu, Z., Lu, Y., Feng, Y., Feng, J., Xia, Y., Tan, R., Cui, F., et al. (2025) · Biomedicines · doi:10.3390/biomedicines13020327 · Cited by 80 · see citing works
“Mitochondrial biogenesis refers to a series of molecular processes of mitochondrial replication, including transcription of nuclear DNA and mitochondrial DNA, protein synthesis, and assembly of respiratory chains, which play an important role in maintaining mitochondrial homeostasis [9].”
µMap proximity labeling in living cells reveals stress granule disassembly mechanisms
Pan, C., Knutson, S. D., Huth, S. W., & MacMillan, D. W. C. (2024) · Nature Chemical Biology · doi:10.1038/s41589-024-01721-2 · Cited by 77 · see citing works
“Autophagy pathways are responsible for recycling larger cellular components and protein aggregates, and their functional integrity is frequently undermined in diseased cells, plausibly leading to the accumulation of these inclusions 14,66 .”
BackgroundNayab, D. E., Din, F. U., Ali, H., Kausar, W. A., Urooj, S., Zafar, M., Khan, I., Shabbir, K., & Khan, G. M. (2023) · Journal of Nanobiotechnology · doi:10.1186/s12951-023-02250-1 · Cited by 68 · see citing works
“ALS is assumed to be carried on by a confluence of genetic, environmental, and dysfunctional aging factors, similar to other neuro-degenerative diseases [57].”
ResultChu, S., Xie, X., Payan, C., & Stochaj, U. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00639-y · Cited by 58 · see citing works
Gao, C., Shi, Q., Pan, X., Chen, J., Zhang, Y., Lang, J., Wen, S., Liu, X., Cheng, T., & Lei, K. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.113892 · Cited by 54 · see citing works
Gomes, L. C., Hänzelmann, S., Hausmann, F., Khatri, R., Moreno, S. O., Parvaz, M., Tzeplaeff, L., Pasetto, L., Gébelin, M., Ebbing, M., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-49196-y · Cited by 56 · see citing works
“8, Supplementary Data 13), since ANXA2 is involved in angiogenesis and autophagy 22 , which are mechanisms known to be altered in ALS 23,24 .”
BackgroundThe panoramic view of amyotrophic lateral sclerosis: A fatal intricate neurological disorder
Dhasmana, S., Dhasmana, A., Narula, A. S., Jaggi, M., Yallapu, M. M., & Chauhan, S. C. (2021) · Life Sciences · doi:10.1016/j.lfs.2021.120156 · Cited by 52 · see citing works
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“PKA signaling has been recently shown to restore synaptic responses in a mouse model of amyotrophic lateral sclerosis (Ba z czyk et al , 2020), a disease that is characterized by defective autophagy, among others (Chua et al , 2021).”
Role of Autophagy Pathway in Parkinson’s Disease and Related Genetic Neurological Disorders
Themistokleous, C., Bagnoli, E., Parulekar, R., & Muqit, M. M. K. (2023) · Journal of Molecular Biology · doi:10.1016/j.jmb.2023.168144 · Cited by 49 · see citing works
Proteostasis disruption and senescence in Alzheimer’s disease pathways to neurodegeneration
Thapa, R., Bhat, A. A., Shahwan, M. J., Ali, H., Padmapriya, G., Bansal, P., Rajotiya, S., Barwal, A., Prasad, G. V. S., Pramanik, A., et al. (2024) · Brain Research · doi:10.1016/j.brainres.2024.149202 · Cited by 44 · see citing works
Liu, F., Morderer, D., Wren, M. C., Vettleson-Trutza, S. A., Wang, Y., Rabichow, B. E., Salemi, M., Phinney, B. S., Oskarsson, B., Dickson, D. W., et al. (2022) · Acta Neuropathologica Communications · doi:10.1186/s40478-022-01322-x · Cited by 42 · see citing works
“Dysfunction of autophagy-related proteins impairs proteostasis and causes neurotoxicity in FTD/ALS, and mutations in both SQSTM1 and VCP can cause ALS and FTD [13].”
BackgroundInfluentialTherapeutic Potential of Polyphenols in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia
Novak, V., Rogelj, B., & Župunski, V. (2021) · Antioxidants · doi:10.3390/antiox10081328 · Cited by 42 · see citing works
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“In genetic results, TBK1 haploinsufficiency has been found to disrupt motor neuron autophagy, enhance mutated SOD1 protein accumulation, and promote ALS-like phenotypes in transgenic mouse models [63].”
BackgroundTargeted drug delivery in neurodegenerative diseases: the role of nanotechnology
Dhariwal, R., Jain, M., Mir, Y. R., Singh, A., Jain, B., Kumar, P., Tariq, M., Verma, D., Deshmukh, K., Yadav, V. K., et al. (2025) · Frontiers in Medicine · doi:10.3389/fmed.2025.1522223 · Cited by 39 · see citing works
“Blood-based biomarkers, retinal imaging biomarkers, and amyloid PET imaging have shown promise in detecting pathological changes associated with conditions like Alzheimer’s disease and Parkinson’s disease (12, 13).”
Hong, D., Zhang, C., Wu, W., Lu, X., & Zhang, L. (2023) · Frontiers in Neurology · doi:10.3389/fneur.2023.1133546 · Cited by 38 · see citing works
Extracellular Vesicles as Potential Biomarkers in Amyotrophic Lateral Sclerosis
Barbo, M., & Ravnik‐Glavač, M. (2023) · Genes · doi:10.3390/genes14020325 · Cited by 38 · see citing works
Autophagy-related proteins: Potential diagnostic and prognostic biomarkers of aging-related diseases
Miceli, C., Leri, M., Stefani, M., & Bucciantini, M. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.101967 · Cited by 39 · see citing works
Induced Pluripotent Stem Cells in Drug Discovery and Neurodegenerative Disease Modelling
Beghini, D. G., Kasai-Brunswick, T. H., & Henriques‐Pons, A. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25042392 · Cited by 35 · see citing works
“It has also been shown that mutations in genes that encode essential autophagy factors impair autophagy and may lead to neurodegenerative conditions such as ALS [105].”
BackgroundParkin and mitochondrial signalling
Connelly, E. M., Frankel, K. S., & Shaw, G. S. (2023) · Cellular Signalling · doi:10.1016/j.cellsig.2023.110631 · Cited by 37 · see citing works
Pathological mechanisms of amyotrophic lateral sclerosis
Hu, Y., Chen, W., Wei, C., Jiang, S., Li, S., Wang, X., & Xu, R. (2023) · Neural Regeneration Research · doi:10.4103/1673-5374.382985 · Cited by 36 · see citing works
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Current insights in the molecular genetic pathogenesis of amyotrophic lateral sclerosis
Zhou, W., & Xu, R. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1189470 · Cited by 35 · see citing works
“The absence of C9orf72 leads to the formation of light chain 3 (LC3)-positive autophagosomes and interferes with the autophagy process (Chua et al., 2022).”
BackgroundMitophagy’s impacts on cancer and neurodegenerative diseases: implications for future therapies
Huang, J. B., Pham, V. T., Fu, S., Huang, G., Liu, Y., & Zheng, L. (2025) · Journal of Hematology & Oncology · doi:10.1186/s13045-025-01727-w · Cited by 38 · see citing works
“Alterations in these proteins may contribute directly to mitophagy defects in ALS [410–412].”
Sattler, R., Traynor, B. J., Robertson, J., Bosch, L. V. D., Barmada, S. J., Svendsen, C. N., Disney, M. D., Gendron, T. F., Wong, P. C., Turner, M. R., et al. (2023) · Neurology and Therapy · doi:10.1007/s40120-023-00548-8 · Cited by 32 · see citing works
“The pathology of C9ORF72-ALS and FTD features a diverse set of protein aggregates, including those composed of SQSTM1/p62, DPRs, and TDP-43 [58].”
BackgroundSelf-citationDiab, R., Pilotto, F., & Saxena, S. (2023) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2023.1086895 · Cited by 31 · see citing works
“In addition, there is coaccumulation of TARDB together with SQSTM1/p62, suggestive of impairments/disturbance in autophagy (Chua et al., 2022).”
BackgroundTherapeutic targeting of ALS pathways: Refocusing an incomplete picture
Maragakis, N. J., de Carvalho, M. A., & Weiss, M. D. (2023) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.51887 · Cited by 31 · see citing works
“148 A few recent clinical trials have targeted aspects of autophagy, so far with largely disappointing results.”
BackgroundCasiraghi, V., Sorce, M. N., Santangelo, S., Invernizzi, S., Bossolasco, P., Lattuada, C., Battaglia, C., Venturin, M., Silani, V., Colombrita, C., et al. (2024) · Experimental Neurology · doi:10.1016/j.expneurol.2024.115057 · Cited by 30 · see citing works
Bakker, R., Ellers, J., Roelofs, D., Vooijs, R., Dijkstra, T. M. H., van Gestel, C. A. M., & Hoedjes, K. M. (2023) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2023.161740 · Cited by 28 · see citing works
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ATG7/GAPLINC/IRF3 axis plays a critical role in regulating pathogenesis of influenza A virus
Chen, B., Guo, G., Wang, G., Zhu, Q., Wang, L., Shi, W., Wang, S., Chen, Y. D., Chi, X., Wen, F., et al. (2024) · PLoS Pathogens · doi:10.1371/journal.ppat.1011958 · Cited by 26 · see citing works
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de Calbiac, H., Renault, S., Haouy, G., Jung, V. A., Roger, K., Zhou, Q., Campanari, M., Chentout, L., Demy, D. L., Marian, A., et al. (2024) · Autophagy · doi:10.1080/15548627.2024.2358736 · Cited by 23 · see citing works
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Brain–body mechanisms contribute to sexual dimorphism in amyotrophic lateral sclerosis
Jacob, S. M., Lee, S., Kim, S. H., Sharkey, K. A., Pfeffer, G., & Nguyen, M. D. (2024) · Nature Reviews Neurology · doi:10.1038/s41582-024-00991-7 · Cited by 25 · see citing works
“The protein functions in a proteosome-mediated degradation pathway and promotes autophagy to remove protein aggregates — two pathways that are defective in ALS 104,105 .”
Guo, X., Zhang, Z., Gu, J., Ke, P., Liu, J., Meng, Y., Zheng, W., Que, W., Fan, R., Luo, J., et al. (2024) · Neurobiology of Disease · doi:10.1016/j.nbd.2024.106534 · Cited by 23 · see citing works
Santarelli, S., Londero, C., Soldano, A., Candelaresi, C., Todeschini, L., Vernizzi, L., & Bellosta, P. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1082047 · Cited by 23 · see citing works
“, 2022), and likewise between glia and neurons to induce survival of neurons (Chua et al., 2022).”
BackgroundMitochondria-associated membrane collapse impairs TBK1-mediated proteostatic stress response in ALS
Watanabe, S., Murata, Y., Oka, Y., Oiwa, K., Horiuchi, M., Iguchi, Y., Komine, O., Sobue, A., Katsuno, M., Ogi, T., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2315347120 · Cited by 23 · see citing works
“The 56 labeled proteins (listed in Dataset S1) were mainly related to the mitochondria [16/56 (29”
BackgroundAdaptive autophagy reprogramming in Schwann cells during peripheral demyelination
Jo, Y. R., Oh, Y., Kim, Y. H., Shin, Y. K., Kim, H. R., Go, H., Shin, J., Park, H. J., Koh, H., Kim, J. K., et al. (2023) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04683-7 · Cited by 20 · see citing works
“For example, autophagy also plays a role in the digestive removal of infectious particles and toxic aggregates [2]; moreover, cells utilize autophagy machinery for the secretion of cytokines, viruses and even intracellular organelles to meet demands for homeostasis [3].”
BackgroundAntisense therapy: a potential breakthrough in the treatment of neurodegenerative diseases
Romanò, R., & Bucci, C. (2023) · Neural Regeneration Research · doi:10.4103/1673-5374.385285 · Cited by 20 · see citing works
Pharmacological and Pathological Implications of Sigma-1 Receptor in Neurodegenerative Diseases
Drewes, N. B., Fang, X., Gupta, N., & Nie, D. (2025) · Biomedicines · doi:10.3390/biomedicines13061409 · Cited by 19 · see citing works
“MAM instability and dysregulated autophagy are key pathological features of ALS [140–142].”
Melatonin Induces Autophagy in Amyotrophic Lateral Sclerosis Mice via Upregulation of SIRT1
Shen, X., Tang, C., Wei, C., Zhu, Y., & Xu, R. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-02875-7 · Cited by 19 · see citing works
“It has been confirmed that autophagy participates in the progression of ALS [23, 43].”
BackgroundZhao, C. F., Xing, Z., Wei, X., Liao, G., Yang, D., Liu, H., & Fan, Y. (2023) · Chemical Engineering Journal · doi:10.1016/j.cej.2023.141730 · Cited by 19 · see citing works
ALS-related p97 R155H mutation disrupts lysophagy in iPSC-derived motor neurons
Klickstein, J. A., Johnson, M. A., Antonoudiou, P., Maguire, J. L., Paulo, J. A., Gygi, S. P., Weihl, C., & Raman, M. (2024) · Stem Cell Reports · doi:10.1016/j.stemcr.2024.01.002 · Cited by 19 · see citing works
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Jamet, M., Dupuis, L., & de Aguilar, J. G. (2024) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2024.1375330 · Cited by 18 · see citing works
“We recommend readers to refer to recent articles published elsewhere that address these topics in detail (Anoar et al., 2021; Chua et al., 2022; Motataianu et al., 2022).”
TDP-43 regulates LC3ylation in neural tissue through ATG4B cryptic splicing inhibition
Torres, P., Rico-Rios, S., Ceron-Codorniu, M., Santacreu-Vilaseca, M., Seoane-Miraz, D., Jad, Y. E., Ayala, V., Mariño, G., Beltran, M., Miralles, M. P., et al. (2024) · Acta Neuropathologica · doi:10.1007/s00401-024-02780-4 · Cited by 18 · see citing works
The Classification and Prediction of Ferroptosis-Related Genes in ALS: A Pilot Study
Zhang, Q.-Q., Zhao, H.-H., Luo, M., Cheng, X., Li, Y., Li, Q.-Y., Wang, Z., & Niu, Q. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.919188 · Cited by 18 · see citing works
Ubiquitin-chains dynamics and its role regulating crucial cellular processes
Gonzalez-Santamarta, M., Bouvier, C., Rodríguez, M. S., & Xolalpa, W. (2021) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2021.11.023 · Cited by 16 · see citing works
Yuan, R., Hahn, Y., Stempel, M. H., Sidibe, D. K., Laxton, O., Chen, J., Kulkarni, A., & Maday, S. (2022) · Autophagy · doi:10.1080/15548627.2022.2084884 · Cited by 18 · see citing works
“ciated with aberrant protein misfolding and aggregation [21,64].”
BackgroundProtein quality control machinery: regulators of condensate architecture and functionality
Rajendran, A., & Castañeda, C. A. (2025) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2024.12.003 · Cited by 16 · see citing works
Advances in the understanding of nuclear pore complexes in human diseases
Li, Y., Zhu, J., Zhai, F., Kong, L., Li, H., & Jin, X. (2024) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-024-05881-5 · Cited by 16 · see citing works
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Beckers, J., & Damme, P. V. (2025) · Autophagy Reports · doi:10.1080/27694127.2025.2474796 · Cited by 16 · see citing works
Genetic architecture of amyotrophic lateral sclerosis: a comprehensive review
Yuan, L., Yang, Y., Guo, Y., & Deng, H. (2025) · Journal of genetics and genomics/Journal of Genetics and Genomics · doi:10.1016/j.jgg.2025.05.008 · Cited by 15 · see citing works
Pramoda, G., Verma, R. K., Kesharwani, P., & Shukla, R. (2025) · Journal of Molecular Liquids · doi:10.1016/j.molliq.2025.127938 · Cited by 15 · see citing works
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Amyotrophic Lateral Sclerosis: Pathophysiological Mechanisms and Treatment Strategies (Part 2)
Tolochko, C., Shiryaeva, O., Alekseeva, T. M., & Dyachuk, V. A. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26115240 · Cited by 13 · see citing works
Cordycepin ameliorates autoimmunity by promoting STING degradation via autophagy pathway
Yang, D., Peng, N., Zhang, H., Qiu, Z.-C., Xu, L., & Pan, M. (2024) · British Journal of Pharmacology · doi:10.1111/bph.17425 · Cited by 13 · see citing works
“…is an evolutionarily conserved degradation process for clearing damaged organelles, intracellular components and foreign pathogens in eukaryotes, which is involved in many physiological and pathological processes (Chua et al., 2022; Lewerissa et al., 2024; Morleo et al., 2023; Pan et al., 2021).”
Gawęda-Walerych, K., Sitek, E. J., Narożańska, E., & Buratti, E. (2021) · Cells · doi:10.3390/cells10123389 · Cited by 13 · see citing works
Invertebrate genetic models of amyotrophic lateral sclerosis
Zhou, L., & Xu, R. (2024) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2024.1328578 · Cited by 12 · see citing works
Proteomic investigation of ALS motor cortex identifies known and novel pathogenetic mechanisms
Lee, A., Henderson, R. D., Arachchige, B. J., Robertson, T., & McCombe, P. (2023) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2023.120753 · Cited by 12 · see citing works
“Some of these molecules, including RET [12], hydrogen peroxide [13], IgF-1 [14], NFE2L2 [15], IL-15 [16], FOXO3 [17] and BACH1 [18] have previously been reported in ALS as potential modifiers capable of influencing disease progression.”
Aberrant protein aggregation in amyotrophic lateral sclerosis
Wang, H., & Zeng, R. (2024) · Journal of Neurology · doi:10.1007/s00415-024-12485-z · Cited by 11 · see citing works
Amyotrophic Lateral Sclerosis (ALS): An Overview of Genetic and Metabolic Signaling Mechanisms
Nogueira‐Machado, J. A., Silva, F. D. C. L. E., Rocha-Silva, F., & Gomes, N. L. (2024) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/0118715273315891240801065231 · Cited by 11 · see citing works
Watanabe, S., & Yamanaka, K. (2025) · BioEssays · doi:10.1002/bies.70016 · Cited by 11 · see citing works
Targeting mitochondrial Ca2+ uptake for the treatment of amyotrophic lateral sclerosis
Zhong, R., Rua, M. T., & Wei‐LaPierre, L. (2023) · The Journal of Physiology · doi:10.1113/jp284143 · Cited by 10 · see citing works
“…through the formation of autophagosomes and regulated by the activation of AMPK, while mitophagy engages in a PTEN induced kinase 1 (PINK)/parkin-mediated signalling pathway and is triggered by mitochondrial membrane depolarization (Chua et al., 2022; Onishi et al., 2021; Seabright & Lai, 2020).”
BackgroundIdera, A., Sharkey, L. M., Kurauchi, Y., Kadoyama, K., Paulson, H. L., Katsuki, H., & Seki, T. (2023) · Journal of Pharmacological Sciences · doi:10.1016/j.jphs.2023.05.002 · Cited by 10 · see citing works
Axonal Degeneration, Impaired Axonal Transport, and Synaptic Dysfunction in Motor Neuron Disorder
Parveen, S., Showkat, F., Badesra, N., Dar, M. S., Maqbool, T., & Dar, M. J. (2024) · Springer eBooks · doi:10.1007/978-981-99-9404-5_8 · Cited by 9 · see citing works
The role of autophagy-lysosomal pathway in motor neuron diseases
Tedesco, B., Ferrari, V., Cozzi, M., Chierichetti, M., Casarotto, E., Pramaggiore, P., Mina, F., Piccolella, M., Cristofani, R., Crippa, V., et al. (2022) · Biochemical Society Transactions · doi:10.1042/bst20220778 · Cited by 9 · see citing works
Protective effects of intrathecal injection of AAV9-RabGGTB-GFP+ in SOD1G93A mice
Gao, T., Huo, J., Xin, C., Yang, J., Liu, Q., Dong, H., Li, R., & Liu, Y. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1092607 · Cited by 9 · see citing works
“Studies have also shown that autophagy plays an important role in the pathogenesis of ALS (Maurel et al., 2018; Chua et al., 2022).”
BackgroundAlessandrini, F., Wright, M., Kurosaki, T., Maquat, L. E., & Kiskinis, E. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.01.31.578311 · Cited by 9 · see citing works
Molecular Visualization of Neuronal TDP43 Pathology In SituPreprint
Erwin, A. L., Fernandez, M. G., Chang, M. L., Attili, D., Bekier, M., Pinarbasi, E. S., Russ, J. E., Sutanto, R., Thomas, D., Shen, X., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.08.19.608477 · Cited by 9 · see citing works
“A Welch’s t-test was performed using GraphPad Prism version 10.1.2 to assess statistical significance.”
InfluentialSelf-citationEmerging roles of RNA binding proteins in intervertebral disc degeneration and osteoarthritis
Li, W., Li, X., Gao, Y., Xiong, C., & Tang, Z. (2023) · Orthopaedic Surgery · doi:10.1111/os.13851 · Cited by 8 · see citing works
“97 Autophagy is associated with multiple human pathologies, including cancer, 98 neurodegeneration, 99 and cardiomyopathic disorders.”
BackgroundAmyotrophic Lateral Sclerosis Mechanism: Insights from the Caenorhabditis elegans Models
Chen, L., Zhang, S., Liu, S., & Gao, S. (2024) · Cells · doi:10.3390/cells13010099 · Cited by 8 · see citing works
“…that SQST-1 operates through an autophagy-independent pathway or alternative mechanisms to ameliorate ALS-related locomotion impairments [104,105]. mechanisms to ameliorate ALS-related locomotion impairments [104,105 The mutation of a single autophagy receptor can induce the decline of…”
BackgroundShen, Y., Li, T., Sun, C., Cheng, X., Chen, Z., Wang, G., & Yang, X. (2024) · Cell Death and Differentiation · doi:10.1038/s41418-024-01330-5 · Cited by 8 · see citing works
“Autophagy plays important roles on maintaining cellular and organismal integrity in response to numerous developmental events or stresses through degrading subcellular components for the reuse and/or redistribution [10].”
Insights into the therapeutic strategies for aging and aging-associated diseases
Dong, R., Wu, Q., Kan, J., Fu, C., Sorrentino, V., Chow, A., Lei, Y., Wu, D., Xu, Z., Du, J., et al. (2026) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-026-02662-z · Cited by 9 · see citing works
“291 Huntington ’ s Disease .”
Liao, Y., Cai, H., Luo, F., Li, D., Li, H., Liao, G., Duan, J., Xu, R., & Zhang, X. (2023) · BMC Medical Genomics · doi:10.1186/s12920-023-01441-x · Cited by 8 · see citing works
“The average survival time of ALS patients is 3–5 years [7].”
BackgroundBroce, I., Sirkis, D. W., Nillo, R. M., Bonham, L. W., Lee, S. E., Miller, B. L., Castruita, P. A., Sturm, V. E., Sugrue, L. P., Desikan, R. S., et al. (2024) · Frontiers in Neuroscience · doi:10.3389/fnins.2024.1258996 · Cited by 7 · see citing works
HLH-30/TFEB modulates autophagy to improve proteostasis in Aβ transgenic Caenorhabditis elegans
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Neurodegeneration, Mitochondria, and Antibiotics
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“Moreover, proteins encoded by the genes C9ORF72, VCP, CHMP2B, VAPB, ALS2, SOD1, and DCTN1 have all been related to vesicular trafficking and may affect autophagy either directly or indirectly [236,237].”
BackgroundA next-generation HDAC6 inhibitor for amyotrophic lateral sclerosis and frontotemporal dementia
James, R. E., Bekier, M. E., Lee, P., Schroeder, F. A., Evans, L. J., Wagner, F. F., Hickman, D., Richardson, T., Hatzipetros, T., Vieira, F. G., et al. (2025) · Brain · doi:10.1093/brain/awaf380 · Cited by 7 · see citing works
“Autophagy is dysregulated in fALS, sALS and FTD, and many of the genetic causes of ALS are related to proteostasis and autophagy factors, 124-126 implicating ALP function as a critical node for therapeutic intervention.”
Self-citationSmeyers, J., Osés-Prieto, J. A., Yadanar, L., Wang, M., Iadarola, M., Lu, S. H.-A., Wang, K. S., Watanabe, T. H., Debnath, J., Burlingame, A. L., et al. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.116494 · Cited by 8 · see citing works
“…targets of TBK1 in Variants in C9ORF72, SQSTM1, and OPTN, encoding autophagy factors, have been consistently associated with familial ALS/FTD. 16,63 We identified novel TBK1-dependent phosphorylation sites in p62/SQSTM1 and in SMCR8, a constitutive C9ORF72-interacting partner that is…”
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SRF deletion results in earlier disease onset in a mouse model of amyotrophic lateral sclerosis
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“Furthermore, autophagy impairment has previously been hypothesized to be mechanistically related to MN vulnerability (43).”
BackgroundHuang, J., Yu, Y., Pang, D., Li, C., Wei, Q., Cheng, Y., Cui, Y., Ou, R., & Shang, H. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03835-5 · Cited by 7 · see citing works
CCDC50 mediates the clearance of protein aggregates to prevent cellular proteotoxicity
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“The UPS is responsible for the clearance of soluble misfolded proteins or mutant monomers, whereas autolysosome-mediated degradation pathway functions as a key catabolic mechanism to clear insoluble protein aggregates [8,9].”
Therapeutic Approaches for C9ORF72-Related ALS: Current Strategies and Future Horizons
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“A hallmark of C9ORF72-associated pathology is the disruption of the autophagic process [50].”
TDP-43 dysfunction compromises UPF1-dependent mRNA metabolism in ALS
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“143,152 The accumulation of ubiquitin and p62 in p-TDP-43-containing skein-like and round hyaline inclusions in sporadic ALS spinal cord neurons could indicate the involvement of impaired autophagy in this disease.”
Potential Diets to Improve Mitochondrial Activity in Amyotrophic Lateral Sclerosis
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“result in the impairment of this process, which can lead to neurodegenerative conditions such as ALS [7].”
BackgroundChen, S., Liu, H., Liu, L., Bai, C., Li, Q., Jiang, L., Ji, Y.-K., Sun, F., Li, X., Gu, X., et al. (2025) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2025.120418 · Cited by 5 · see citing works
miR-142-3p alleviates neuronal apoptosis in Parkinson’s disease via negatively regulating C9orf72
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TBK1 is involved in programmed cell death and ALS-related pathways in novel zebrafish models
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“TBK1 is a known regulator of autophagy that phosphorylates and controls the activity of the cargo proteins p62, OPTN, NDP52 and interacts with the ULK1 initiation complex [2, 3].”
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- Authors
- Chua, J. P., De Calbiac, H., Kabashi, E., & Barmada, S. J.
- Affiliations
- University of Michigan (US)
- Recherche translationnelle sur les maladies neurologiques, Institut Imagine, UMR-1163 INSERM et Université Paris Descartes, Hôpital Universitaire Necker-Enfants Malades, Paris, France
- Hôpital Necker-Enfants Malades (FR)
- Corresponding author
- Barmada, Sami J.
- Venue
- Autophagy
- Publisher
- Informa UK Limited
- Published
- 2021-05-31
- Volume
- 18
- Issue
- 2
- Pages
- 254-282
- ISSN
- 1554-8627 (ISSN-L)
- 1554-8635
- PMC
- PMC8942428
- OpenAlex
- W3164735937
- Cited by
- 189
- References
- 527
- Citations by year
- 2026: 34 · 2025: 51 · 2024: 46 · 2023: 34 · 2022: 19 · 2021: 5
- FWCI
- 3.39
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Autophagy (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (2R25NS089450-06)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- amyotrophic lateral sclerosis, CHMP2B, dipeptide repeat proteins, PINK1, mTOR, TBK1, TFEB, LC3, VCP, ubiquitin-proteasome system, unfolded protein response, frontotemporal dementia, autophagy-related proteins, therapeutic target
- MeSH terms
- Proteostasis, Amyotrophic Lateral Sclerosis, Autophagy, Humans, Unfolded Protein Response, Frontotemporal Dementia
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