Autophagy and ALS: mechanistic insights and therapeutic implications

In the paper

“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.”

What the sources say

• Not checked yetcites [11] source
• Not checked yetcites [12] source
• Not checked yetcites [13] source
• Not checked yetcites [14] source
• Not checked yetcites [15] source
• Not checked yetcites [16] source
• Not checked yetcites [17] source
• Not checked yetcites [18] source
• Not checked yetcites [19] Spaulding HR, 2020, Physiol Rep source
• Not checked yetcites [20] source

In the paper

“Macroautophagy, often referred to simply as autophagy, is an evolutionarily conserved eukaryotic pathway for bulk and selective degradation of proteins and organelles [31].”

What the sources say

• Not checked yetcites [31] source

In the paper

“ALS-FTD-associated SQSTM1 mutations frequently affect the UBA and LIR domains involved in autophagy and include both missense and nonsense mutations [123–125].”

What the sources say

• Not checked yetcites [123] Le Ber I, 2013, JAMA Neurol
• Not checked yetcites [124] source
• Not checked yetcites [125] source

In the paper

“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].”

What the sources say

• Not checked yetcites [138] Daroszewska A, 2011, Hum Mol Genet source
• Not checked yetcites [139] Kurihara N, 2007, J Clin Invest source
• Not checked yetcites [140] source

In the paper

“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].”

What the sources say

• Not checked yetcites [36] source
• Not checked yetcites [37] source

In the paper

“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].”

What the sources say

• Not checked yetcites [45] source
• Not checked yetcites [46] source

In the paper

“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].”

What the sources say

• Not checked yetcites [58] source
• Not checked yetcites [59] source

In the paper

“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].”

What the sources say

• Not checked yetcites [141] source
• Not checked yetcites [142] source

In the paper

“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].”

What the sources say

• Not checked yetcites [41] source

In the paper

“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].”

What the sources say

• Not checked yetcites [137] source

In the paper

“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].”

What the sources say

• Not checked yetcites [123] Le Ber I, 2013, JAMA Neurol
• Not checked yetcites [124] source
• Not checked yetcites [125] source
• Not checked yetcites [126] source
• Not checked yetcites [127] source
• Not checked yetcites [128] source

In the paper

“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].”

What the sources say

• Not checked yetcites [130] source
• Not checked yetcites [84] source
• Not checked yetcites [131] source

In the paper

“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].”

What the sources say

• Not checked yetcites [47] source
• Not checked yetcites [48] source

In the paper

“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).”

What the sources say

• Not checked yetcites [82] Lorente Pons A, 2020, J Pathol source
• Not checked yetcites [116] source
• Not checked yetcites [117] source
• Not checked yetcites [118] source

In the paper

“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”

What the sources say

• Not checked yetcites [74] source
• Not checked yetcites [75] source
• Not checked yetcites [76] source
• Not checked yetcites [77] source
• Not checked yetcites [78] source
• Not checked yetcites [79] source
• Not checked yetcites [80] source
• Not checked yetcites [81] source

In the paper

“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].”

What the sources say

• Not checked yetcites [134] source
• Not checked yetcites [135] source
• Not checked yetcites [136] source

In the paper

“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].”

What the sources say

• Not checked yetcites [38] source
• Not checked yetcites [39] source

In the paper

“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].”

What the sources say

• Not checked yetcites [60] source

In the paper

“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].”

What the sources say

• Not checked yetcites [40] source
• Not checked yetcites [41] source

In the paper

“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].”

What the sources say

• Not checked yetcites [184] Atanasio A, 2016, Sci Rep source
• Not checked yetcites [185] source
• Not checked yetcites [186] O’Rourke JG, 2015, Neuron source
• Not checked yetcites [187] Sudria-Lopez E, 2016, Acta Neuropathol source

In the paper

“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.”

What the sources say

• Not checked yetcites [181] Madill M, 2017, Mol Brain source

In the paper

“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].”

What the sources say

• Not checked yetcites [192] source

In the paper

“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].”

What the sources say

• Not checked yetcites [179] source
• Not checked yetcites [180] source

In the paper

“While c9orf72 knockout animals exhibit a shortened lifespan [184,185,187], no specific neuronal defects have been identified in these mice.”

What the sources say

• Not checked yetcites [184] Atanasio A, 2016, Sci Rep source
• Not checked yetcites [185] source
• Not checked yetcites [187] Sudria-Lopez E, 2016, Acta Neuropathol source

In the paper

“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].”

What the sources say

• Not checked yetcites [143] source
• Not checked yetcites [144] source
• Not checked yetcites [145] source

In the paper

“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].”

What the sources say

• Not checked yetcites [193] source

In the paper

“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.”

What the sources say

• Not checked yetcites [182] Ciura S, 2013, Ann Neurol source
• Not checked yetcites [183] source

In the paper

“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.”

What the sources say

• Not checked yetcites [148] source
• Not checked yetcites [154] source

In the paper

“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].”

What the sources say

• Not checked yetcites [155] Anor CJ, 2015, Neurobiol Aging
• Not checked yetcites [156] source
• Not checked yetcites [157] Cacace R, 2013, Neurobiol Aging source
• Not checked yetcites [158] Harms M, 2013, JAMA Neurol source
• Not checked yetcites [159] Kostić VS, 2014, J Neurol source
• Not checked yetcites [160] Lesage S, 2013, Brain source
• Not checked yetcites [161] source
• Not checked yetcites [162] source
• Not checked yetcites [163] O’Dowd S, 2012, Mov Disord source
• Not checked yetcites [164] Hensman Moss DJ, 2014, Neurology source

In the paper

“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].”

What the sources say

• Not checked yetcites [146] source
• Not checked yetcites [147] Amick J, 2018, Mol Biol Cell source
• Not checked yetcites [148] source
• Not checked yetcites [149] source
• Not checked yetcites [150] source

In the paper

“C9orf72 mutations are associated with reduced basal autophagy and enhanced sensitivity to autophagy inhibitors in human iPSC-derived neurons [153,178].”

What the sources say

• Not checked yetcites [153] source
• Not checked yetcites [178] source

In the paper

“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.”

What the sources say

• Not checked yetcites [171] source
• Not checked yetcites [174] Davidson Y, 2016, Neuropathol Appl Neurobiol source
• Not checked yetcites [175] source
• Not checked yetcites [176] Gomez-Deza J, 2015, Acta Neuropathol Commun source
• Not checked yetcites [177] source

In the paper

“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].”

What the sources say

• Not checked yetcites [154] source
• Not checked yetcites [188] Devlin AC, 2015, Nat Commun source
• Not checked yetcites [189] source
• Not checked yetcites [190] source
• Not checked yetcites [191] source

In the paper

“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].”

What the sources say

• Not checked yetcites [238] source
• Not checked yetcites [239] source

In the paper

“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).”

What the sources say

• Not checked yetcites [212] source
• Not checked yetcites [213] source

In the paper

“TBK1 also phosphorylates SMCR8, which forms a complex with C9orf72 and WDR41, thereby enhancing autophagy initiation [148].”

What the sources say

• Not checked yetcites [148] source

In the paper

“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.”

What the sources say

• Not checked yetcites [148] source

In the paper

“this effect is exacerbated by genetic loss of ATG5, enhancing stress granule accumulation and, ultimately, leading to cell death [235].”

What the sources say

• Not checked yetcites [235] source

In the paper

“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.”

In the paper

“Conversely, rapamycin-mediated activation of autophagy ameliorates these features, suggesting that FUS-positive inclusions are autophagy substrates [235].”

What the sources say

• Not checked yetcites [235] source

In the paper

“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].”

What the sources say

• Not checked yetcites [206] source
• Not checked yetcites [210] source
• Not checked yetcites [211] source
• Not checked yetcites [205] source

In the paper

“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].”

What the sources say

• Not checked yetcites [232] Dormann D, 2012, Embo J source
• Not checked yetcites [233] source
• Not checked yetcites [234] source

In the paper

“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].”

What the sources say

• Not checked yetcites [214] source
• Not checked yetcites [215] source

In the paper

“UBQLN2 modulates MTORC1 activity, lysosomal acidification, and, in turn, autophagosome maturation [229–231].”

What the sources say

• Not checked yetcites [229] source
• Not checked yetcites [230] source
• Not checked yetcites [231] Yang W, 2020, S NPJ Parkinsons Dis source

In the paper

“while also triggering intracellular inclusions [226,227] and motor defects in vitro and in vivo [226].”

What the sources say

• Not checked yetcites [226] source
• Not checked yetcites [227] source

In the paper

“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].”

What the sources say

• Not checked yetcites [218] Walters KJ, 2004, Biochim Biophys Acta source

In the paper

“In rats, overexpression of ALS mutant UBQLN2 leads to motor neuron loss and accumulation of autophagy substrates such as SQSTM1 and LC3-II [228].”

What the sources say

• Not checked yetcites [228] source

In the paper

“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].”

What the sources say

• Not checked yetcites [253] source

In the paper

“Transgenic mice expressing mutant CHMP2B develop progressive neurological defects, axonal pathology, early mortality and neuronal loss reminiscent of FTD [270,271].”

What the sources say

• Not checked yetcites [270] Clayton EL, 2017, Hum Mol Genet
• Not checked yetcites [271] source

In the paper

“overexpression of CHMP2B mutants leads to the formation of large cytoplasmic vacuoles and increased LC3-II protein levels [266]”

What the sources say

• Not checked yetcites [266] Cox LE, 2010, PLoS One source

In the paper

“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].”

What the sources say

• Not checked yetcites [272] source
• Not checked yetcites [270] Clayton EL, 2017, Hum Mol Genet

In the paper

“In IBMPFD murine muscle lysates, VCP mutations disrupt autophagosome maturation and fusion with lysosomes, but not the formation of early autophagosome precursors [246,249].”

What the sources say

• Not checked yetcites [246] source
• Not checked yetcites [249] source

In the paper

“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].”

What the sources say

• Not checked yetcites [266] Cox LE, 2010, PLoS One source

In the paper

“Genetic analyses have uncovered >20 OPTN mutations in ALS patient cohorts, accounting for ~3% of familial disease and ~1% of sporadic disease [258].”

What the sources say

• Not checked yetcites [258] source

In the paper

“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].”

What the sources say

• Not checked yetcites [263] source

In the paper

“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].”

What the sources say

• Not checked yetcites [252] Hall CE, 2017, Cell Rep source

In the paper

“SQSTM1-positive inclusions are also ubiquitin-positive, consistent with a disruption in the UPS [118].”

What the sources say

• Not checked yetcites [118] source

In the paper

“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].”

What the sources say

• Not checked yetcites [267] source

In the paper

“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].”

What the sources say

• Not checked yetcites [256] source

In the paper

“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].”

What the sources say

• Not checked yetcites [194] source
• Not checked yetcites [254] source
• Not checked yetcites [255] source

In the paper

“the majority of pathogenic OPTN mutations are located in its UBAN domain and may impair ubiquitin binding [259]”

What the sources say

• Not checked yetcites [259] source

In the paper

“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].”

What the sources say

• Not checked yetcites [264] source
• Not checked yetcites [265] Van Der Zee J, 2008, Hum Mol Genet source
• Not checked yetcites [268] source

In the paper

“but are also responsible for ~1-2% of familial ALS cases [241–243].”

What the sources say

• Not checked yetcites [241] source
• Not checked yetcites [242] Koppers M, 2013, Neurobiol Aging source
• Not checked yetcites [243] source

In the paper

“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.”

In the paper

“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].”

What the sources say

• Not checked yetcites [290] source
• Not checked yetcites [291] source
• Not checked yetcites [292] source
• Not checked yetcites [293] source

In the paper

“suggest that correcting autophagy dysregulation or promoting the autophagic degradation of TARDBP may be of therapeutic benefit in ALS.”

In the paper

“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.”

What the sources say

• Not checked yetcites [335] source

In the paper

“overexpression of TFEB enhances LC3 expression and prevents cytotoxicity in SOD1G93A-expressing NSC-34 cells [362].”

What the sources say

• Not checked yetcites [362] Chen Y, 2015, Am J Transl Res

In the paper

“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].”

What the sources say

• Not checked yetcites [357] source

In the paper

“the phosphodiesterase inhibitor ibudilast induces autophagy by promoting TFEB activity, which enhances clearance of TARDBP aggregates and reduces cytotoxicity [360].”

What the sources say

• Not checked yetcites [360] source

In the paper

“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].”

What the sources say

• Not checked yetcites [296] source

In the paper

“embryonic stem cell-derived motor neurons expressing TARDBPN390D show increased levels of the autophagy suppressor, BCL2, and reduced autophagic activity [300].”

What the sources say

• Not checked yetcites [300] Huang SL, 2020, Acta Neuropathol Commun source

In the paper

“suggesting that these chaperones are key suppressors of autophagy and may accentuate TARDBP-related toxicity in ALS [354].”

What the sources say

• Not checked yetcites [354] source

In the paper

“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].”

What the sources say

• Not checked yetcites [350] source

In the paper

“conditional deletion of Atg7 in mouse motor neurons accentuates early ALS pathology but mitigates glial inflammation and early death [336].”

What the sources say

• Not checked yetcites [336] source

In the paper

“autophagy helps eliminate synapses during development [377,378]”

What the sources say

• Not checked yetcites [377] source
• Not checked yetcites [378] source

In the paper

“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].”

What the sources say

• Not checked yetcites [370] source
• Not checked yetcites [372] source
• Not checked yetcites [374] source

In the paper

“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].”

What the sources say

• Not checked yetcites [379] source

In the paper

“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].”

What the sources say

• Not checked yetcites [24] source
• Not checked yetcites [22] source
• Not checked yetcites [25] source

In the paper

“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].”

What the sources say

• Not checked yetcites [380] source
• Not checked yetcites [381] source

In the paper

“OPTN mutations produce microglial activation and glaucoma [288]”

What the sources say

• Not checked yetcites [288] source

In the paper

“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.”

In the paper

“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].”

What the sources say

• Not checked yetcites [385] source
• Not checked yetcites [386] Fox JH, 2010, Mol Neurodegener source
• Not checked yetcites [387] source
• Not checked yetcites [384] source

In the paper

“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].”

What the sources say

• Not checked yetcites [382] source

In the paper

“rapamycin and related MTOR inhibitors, as well as AKT inhibitors, are ineffective inducers of neuronal autophagy [338,384].”

What the sources say

• Not checked yetcites [338] source
• Not checked yetcites [384] source

In the paper

“C9orf72 deficiency leads to lymphocytic inflammation, lymphadenopathy, and splenomegaly [149]”

What the sources say

• Not checked yetcites [149] source

In the paper

“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].”

What the sources say

• Not checked yetcites [214] source

In the paper

“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].”

What the sources say

• Not checked yetcites [400] source

In the paper

“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].”

What the sources say

• Not checked yetcites [417] source
• Not checked yetcites [418] source
• Not checked yetcites [419] source

In the paper

“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].”

What the sources say

• Not checked yetcites [416] source
• Not checked yetcites [417] source

In the paper

“Autophagy and phagocytosis share key morphological and mechanistic features [428].”

What the sources say

• Not checked yetcites [428] source

In the paper

“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].”

What the sources say

• Not checked yetcites [11] source

In the paper

“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].”

What the sources say

• Not checked yetcites [401] source

In the paper

“For instance, both pathways rely on vesicular structures to deliver contents to lysosomes for degradation.”

What the sources say

• Not checked yetcites [428] source

In the paper

“not only is autophagy responsible for degrading HTT in astrocytes, but it also promotes glutamate transporter expression in these cells [413]”

What the sources say

• Not checked yetcites [413] source

In the paper

“implying that astrocytes are both necessary and sufficient for neurodegeneration in this ALS model.”

What the sources say

• Not checked yetcites [414] source
• Not checked yetcites [181] Madill M, 2017, Mol Brain source
• Not checked yetcites [415] source

In the paper

“these compounds are sufficient to reduce TARDBPM337V-associated toxicity in iPSC-derived astrocytes [357], presumably through autophagy upregulation.”

What the sources say

• Not checked yetcites [357] source

In the paper

“In transgenic mice overexpressing mutant SOD1 associated with ALS, astrocytes display more SOD1-positive inclusions than do neurons, and at an earlier stage [414].”

What the sources say

• Not checked yetcites [414] source

In the paper

“Conditional oligodendrocyte-specific deletion of Atg5 in mice leads to incomplete differentiation, reduced myelination, abnormal myelin compaction, oligodendrocytic death, and shortened life span [444].”

What the sources say

• Not checked yetcites [444] Bankston AN, 2019, Glia source

In the paper

“C9orf72-deficient mice display lysosomal accumulation and a hyperactive immune response characterized by enhanced production of IL1B and IL6 [184,185,187,439],”

What the sources say

• Not checked yetcites [184] Atanasio A, 2016, Sci Rep source
• Not checked yetcites [185] source
• Not checked yetcites [187] Sudria-Lopez E, 2016, Acta Neuropathol source
• Not checked yetcites [439] source

In the paper

“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].”

What the sources say

• Not checked yetcites [444] Bankston AN, 2019, Glia source

In the paper

“Consistent with these findings, autophagy activation enhances oligodendrocyte survival and promotes myelination in a rat model of demyelinating disease [448].”

What the sources say

• Not checked yetcites [448] source

In the paper

“Collectively, these findings reinforce the convergence between inflammation and autophagy in microglia, and their importance for ALS pathogenesis.”

In the paper

“and conditional Atg7 deletion in mouse Schwann cells leads to cytoplasmic swelling, ribosomal accumulation, dysmorphic ER, and dysmyelination [459].”

What the sources say

• Not checked yetcites [459] source

In the paper

“but rapamycin fails to enhance recovery [449] despite effective stimulation of autophagy in these cells [449–451].”

What the sources say

• Not checked yetcites [449] source
• Not checked yetcites [450] source
• Not checked yetcites [451] Riedel M, 2010, PLoS One source

In the paper

“Paradoxically, suppression of autophagy with NTF3 (neurotrophin 3) disinhibits oligodendrocyte proliferation and promotes motor recovery in a separate model of spinal cord contusion [452].”

What the sources say

• Not checked yetcites [452] source

In the paper

“In addition, oligodendrocyte autophagy, OPC differentiation, and myelination during development are all regulated by MTOR [445–447].”

What the sources say

• Not checked yetcites [445] source
• Not checked yetcites [446] source
• Not checked yetcites [447] Tyler WA, 2009, J Neurosci source

In the paper

“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].”

What the sources say

• Not checked yetcites [461] Zhang SJ, 2019, Biochem Biophys Res Commun source

In the paper

“For instance, centronuclear myopathy is caused by mutations in the genes encoding MTM1 (myotubularin1) or MTMR14/Jumpy (myotubularin related protein 14) [17,20].”

What the sources say

• Not checked yetcites [17] source
• Not checked yetcites [20] source

In the paper

“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].”

What the sources say

• Not checked yetcites [482] source

In the paper

“neurogenic atrophy can be partially mitigated by adrenergic stimulation, which activates autophagy through Atg7 and counteracts denervation-induced inhibition of autophagic flux [474].”

What the sources say

• Not checked yetcites [474] source

In the paper

“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].”

What the sources say

• Not checked yetcites [473] source

In the paper

“Conversely, stimulating Schwann cell autophagy with rapamycin promotes myelination and improves peripheral nerve regeneration [465,466].”

What the sources say

• Not checked yetcites [465] source
• Not checked yetcites [466] source

In the paper

“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.”

In the paper

“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].”

What the sources say

• Not checked yetcites [460] source

In the paper

“In ALS, skeletal muscle-specific expression of SOD1G93A is associated with atrophy and elevated autophagy [479],”

What the sources say

• Not checked yetcites [479] source

In the paper

“Similar effects have been seen in humans and mice after strenuous exercise, interpreted as a response to exercise-related muscle breakdown [482,483].”

What the sources say

• Not checked yetcites [482] source
• Not checked yetcites [483] source

In the paper

“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.”

In the paper

“These loss-of-function mutations prevent these enzymes from metabolizing phosphoinositides required for autophagy, thereby disinhibiting autophagy flux and muscle atrophy [17,20].”

What the sources say

• Not checked yetcites [17] source
• Not checked yetcites [20] source

In the paper

“Conversely, genetic ablation of RUNX1 disinhibits autophagy and worsens atrophy [472].”

What the sources say

• Not checked yetcites [472] source

In the paper

“and conditional Atg7 deletion in mouse skeletal muscle leads to atrophy, weakness, and accumulation of unhealthy mitochondria and sarcoplasmic reticulum [477].”

What the sources say

• Not checked yetcites [477] source

In the paper

“skeletal muscle denervation causes neurogenic atrophy and may activate autophagy;”

What the sources say

• Not checked yetcites [472] source

In the paper

“Aged rats also show elevated basal mitophagy, higher levels of mitophagy proteins, higher TFEB expression and lysosomal markers than young mice;”

What the sources say

• Not checked yetcites [497] source

In the paper

“On the other hand, sarcopenia involves autophagy of muscle structural components, and attenuation of autophagy with PPARGC1A overexpression mitigates sarcopenia [495].”

What the sources say

• Not checked yetcites [495] source

In the paper

“These negative trials, together with lithium’s narrow therapeutic index, severely limit the therapeutic utility of lithium for ALS (Figure 3).”

In the paper

“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).”

In the paper

“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].”

What the sources say

• Not checked yetcites [491] source

In the paper

“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].”

What the sources say

• Not checked yetcites [505] source
• Not checked yetcites [506] source
• Not checked yetcites [507] source
• Not checked yetcites [508] source
• Not checked yetcites [509] source
• Not checked yetcites [510] source
• Not checked yetcites [511] source

In the paper

“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.”

In the paper

“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].”

What the sources say

• Not checked yetcites [490] source