The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases

Lysosomes are required for turnover of damaged, misfolded and aggregated proteins as part of proteostasis.

“As part of the normal process of protein homeostasis (i.e., proteostasis), lysosomes are required for turnover of damaged, misfolded and aggregated proteins.2”

• cites [2] Alaamery, 2021, Role of Sphingolipid Metabolism in Neurodegeneration, J. Neurochem. sourcePartly supported

  The Introduction section on sphingosine-1-phosphate in neurodegeneration says autophagy helps prevent the accumulation of misfolded proteins in neurons. It does not state that lysosomes are required for this turnover or specifically address damaged and aggregated proteins in that context (no page number is available in our copy). (LLM, conf=0.82)

  Experimental — accuracy not yet measured

Possession of a single mutant allele responsible for certain childhood lysosomal disorders increases risk for a range of adult neurodegenerative disorders, including Alzheimer's disease, frontotemporal dementia and Parkinson's disease.

“We now know that possession of a single mutant allele responsible for certain childhood disorders—those involving the lysosome—increases risk for a range of adult neurodegenerative disorders, including Alzheimer’s disease (AD), frontotemporal dementia (FTD) and Parkinson’s disease (PD).5,7”

• cites [5] Almacellas, 2021, Lysosomal degradation ensures accurate chromosomal segregation to prevent chromosomal instability, Autophagy sourceCould not verify

  The Results and Discussion passages address lysosomal degradation during mitosis and chromosomal instability, not inherited lysosomal disorders or adult neurodegenerative risk. Searches for single mutant alleles, lysosomal disorders, and Alzheimer’s, frontotemporal dementia, and Parkinson’s disease found no passage in our copy supporting the claim. (LLM, conf=0.78)

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• cites [7] Alquezar, 2020, Heavy metals contaminating the environment of a progressive supranuclear palsy cluster induce tau accumulation and cell death in cultured neurons, Sci. Rep. 2020 10 sourceCould not verify

  The Introduction discusses genetic variants in progressive supranuclear palsy, and the Results describe neurons carrying a heterozygous MAPT mutation. Neither passage addresses whether carrying one allele for a childhood lysosomal disorder increases risk of Alzheimer’s disease, frontotemporal dementia or Parkinson’s disease. Searches for lysosomal disorders and single-allele carrier risk found no passage making that link. (LLM, conf=0.76)

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Kufor-Rakeb syndrome can present in adulthood, quite late for a neurodevelopmental disorder.

“It can present in adulthood, quite late for a neurodevelopmental disorder.62,63”

• cites [62] Geisler, 2010, The PINK1/Parkin-mediated mitophagy is compromised by PD-associated mutations, Autophagy sourceCould not verify

  The Introduction and Discussion address PINK1/Parkin-mediated mitophagy and Parkinson disease, not the age at which Kufor-Rakeb syndrome presents. Searches for Kufor-Rakeb syndrome, adult onset, and ATP13A2 found no passage addressing the claim; the paper’s references to early-onset parkinsonism concern PINK1. (LLM, conf=0.76)

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• cites [63] Ghavami, 2014, Autophagy and apoptosis dysfunction in neurodegenerative disorders, Prog. Neurobiol. sourceCould not verify

  The Parkinson’s disease section discusses variable onset ages in inherited Parkinson’s disease, but does not address Kufor-Rakeb syndrome specifically. Searches for Kufor-Rakeb, ATP13A2/PARK9, and adult presentation of a neurodevelopmental disorder found no passage establishing the claim in our copy. (LLM, conf=0.76)

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In yeast and C. elegans, lysosomal pH becomes more alkaline with age.

“In yeast and C. elegans, lysosomal pH becomes more alkaline with age.56,57”

• cites [56] Fujii, 2023, Parkinson’s disease-associated ATP13A2/PARK9 functions as a lysosomal H+,K+-ATPase, Nat. Commun. 2023 14 sourceCould not verify

  The Results section reports lysosomal alkalinization after ATP13A2 inhibition in human cells, not a change with age in yeast or C. elegans. Searches for yeast, C. elegans, aging, and lysosomal pH found no passage in our copy addressing the attributed claim; page numbers were unavailable. (LLM, conf=0.77)

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• cites [57] Fuller, 2006, Epidemiology of lysosomal storage diseases: an overview, Fabry Dis. Perspect. 5 Years FOSNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Amyloid beta accumulation in neurons in mouse models of AD results in faulty lysosomal acidification.

“In particular, amyloid beta accumulation in neurons in mouse models of AD has been shown to result in faulty lysosomal acidification.60”

• cites [60] Geier, 2019, Rare variants in the neuronal ceroid lipofuscinosis gene MFSD8 are candidate risk factors for frontotemporal dementia, Acta Neuropathol. sourceCould not verify

  The Results section on lysosomal malfunctioning reports impaired lysosomal degradation in cells from people carrying MFSD8 variants, not faulty lysosomal acidification in neurons of Alzheimer’s mouse models. Searches for amyloid beta, Alzheimer’s mouse models, and lysosomal acidification found no passage in our copy addressing the claimed causal relationship; page numbers were not available. (LLM, conf=0.76)

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The balance between cell proliferation and programmed cell death is altered in LSDs as well as neurodegenerative disorders.

“The balance between cell proliferation and programmed cell death is altered in LSDs as well as neurodegenerative disorders.26,27”

• cites [26] Butler, 2019, Multi-Granulin Domain Peptides Bind to Pro-Cathepsin D and Stimulate Its Enzymatic Activity More Effectively Than Progranulin in Vitro, Biochemistry sourceCould not verify

  The paper’s Abstract discusses progranulin, lysosomal function, and neurodegenerative disease, and mentions that granulins may affect cell growth. It does not address whether the balance between cell proliferation and programmed cell death is altered in lysosomal storage diseases or neurodegenerative disorders. Searches for that balance and for apoptosis in those diseases found no supporting passage in our copy. (LLM, conf=0.74)

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• cites [27] Caballero, 2021, Acetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice, Nat. Commun. sourceCould not verify

  The Results section, “CMA dynamics are altered in AD patient brains” (page unavailable), reports impaired chaperone-mediated autophagy in Alzheimer’s disease, not a change in the balance between cell proliferation and programmed cell death. Searches for that balance, apoptosis, and lysosomal storage disorders found no passage in our copy addressing the claim. (LLM, conf=0.76)

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During division of NSCs, lysosomes are asymmetrically distributed between daughter cells.

“During division of NSCs, lysosomes are asymmetrically distributed between daughter cells.”

• cites [18] Ben-Zvi, 2009, Collapse of proteostasis represents an early molecular event in Caenorhabditis elegans aging, Proc. Natl. Acad. Sci. USA sourceCould not verify

  The Results discuss dynamin function in C. elegans neurons and coelomocytes during aging, not neural stem-cell division. Searches for lysosomes, asymmetric segregation, and daughter cells found no passage addressing the claim; page numbers are unavailable in our copy. (LLM, conf=0.78)

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As CNS develops, asymmetrical division of neural stem cells is required for differentiation and migration into complex cellular subtypes and circuits.

“As the CNS develops, asymmetrical division of neural stem cells (NSCs) is required for the differentiation and migration into the complex cellular subtypes and circuits of the brain.”

• cites [17] Bellenguez, 2022, New insights into the genetic etiology of Alzheimer’s disease and related dementias, Nat. Genet sourceCould not verify

  The Methods section, “Expression in various cell types” (page unavailable), describes cell classes in adult brain tissue, while the Pathway analyses concern Alzheimer’s disease risk. Searches for asymmetric neural stem-cell division and embryonic brain development found no passage addressing whether that division is required for differentiation or migration during CNS development. (LLM, conf=0.74)

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These processes require the activity of Notch proteins.

“These processes require the activity of Notch proteins, transmembrane receptors vital to embryonic development and self-renewal systems.17”

• cites [17] Bellenguez, 2022, New insights into the genetic etiology of Alzheimer’s disease and related dementias, Nat. Genet sourceCould not verify

  The Gene prioritization and Discussion passages discuss TNF signaling, LUBAC, and microglial activation, not Notch proteins. Searches for “Notch” and for embryonic development and self-renewal found no passage in our copy stating that these processes require Notch activity. (LLM, conf=0.76)

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Partial inhibition of mTOR can pause mouse blastocyst development, preserving stemness for weeks in culture.

“Partial inhibition of mTOR, which mimics nutrient starvation and activates autophagy, can pause mouse blastocyst development, preserving “stemness” for weeks in culture.16”

• cites [16] Beccari, 2023, Microglial phagocytosis dysfunction in stroke is driven by energy depletion and induction of autophagy, Autophagy sourceCould not verify

  The Results section, “Rapamycin prevents phagocytosis impairment” (page unavailable), discusses mTOR inhibition and autophagy in a mouse stroke model. Searches for blastocysts, stemness, and paused embryonic development found no passage in our copy addressing whether mTOR inhibition preserves mouse blastocysts for weeks in culture. (LLM, conf=0.78)

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Defective myelination is a feature of many LSDs, as well as neurodegeneration.

“Thus, defective myelination is a feature of many LSDs, as well as neurodegeneration,39”

• cites [39] Cuanalo-Contreras, 2023, Extensive accumulation of misfolded protein aggregates during natural aging and senescence, Front Aging Neurosci. sourceCould not verify

  The Introduction and Discussion discuss protein misfolding, aging, and neurodegeneration, but do not link defective myelination to neurodegeneration or lysosomal storage diseases. Searches for myelin, myelination, oligodendrocytes, and lysosomal storage diseases found no passage addressing the claim; page numbers were not available in our copy. (LLM, conf=0.76)

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Impairment of mitophagy has been implicated in disease through strong genetic links with PD, specifically the genes LRRK2, PARKIN, and PINK1.

“Impairment of mitophagy has been implicated in disease through strong genetic links with PD, specifically the genes LRRK2, PARKIN, and PINK1.51–55”

• cites [51] Du, 2025, Small-molecule activation of TFEB alleviates Niemann–Pick disease type C via promoting lysosomal exocytosis and biogenesis, Elife sourceCould not verify

  The Introduction (page unavailable) discusses TFEB, autophagy, and Parkinson’s disease, while the References list a study of mitophagy downstream of Parkin. Neither passage states that impaired mitophagy is genetically linked to Parkinson’s disease through LRRK2, PARKIN, and PINK1. Searches for those genes and the claimed genetic link found no supporting passage in our copy. (LLM, conf=0.72)

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• cites [52] Ellis, 1986, Genetic control of programmed cell death in the nematode C. elegans, Cell sourceNot checked — no full text of the source
• cites [53] Farfel-Becker, 2019, Neuronal Soma-Derived Degradative Lysosomes Are Continuously Delivered to Distal Axons to Maintain Local Degradation Capacity, Cell Rep. sourceCould not verify

  The Results section links impaired axonal lysosome delivery to accumulation of a Parkinson’s-associated α-synuclein mutant, not to impaired mitophagy or genetic risk from LRRK2, PARKIN, and PINK1. The References list names a study of PINK1- and Parkin-dependent mitophagy, but our copy does not make the claimed genetic link to Parkinson’s disease; a search for LRRK2 found no relevant passage. No page numbers are available in our copy. (LLM, conf=0.76)

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• cites [54] Feldmann, 2011, Transport of the major myelin proteolipid protein is directed by VAMP3 and VAMP7, J. Neurosci. sourceCould not verify

  Our copy’s sections on VAMP3/VAMP7-dependent transport and myelination address proteolipid trafficking, not mitophagy or Parkinson’s disease. Searches for mitophagy, PD, LRRK2, PARKIN, and PINK1 found no passage supporting the claimed genetic links; no page numbers were available in the indexed passages. (LLM, conf=0.78)

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• cites [55] Ferreira, 2023, Lysosomal Storage Disease, Metabolic Diseases Foundations Clinical Management Genetics PathologyNot checked yet

  Not checked in the free run.

Lysosomes are important in apoptosis, a form of programmed cell death requisite for appropriate development of the mammalian nervous system.

“Lysosomes are also important in apoptosis, a form of programmed cell death (PCD) that is requisite for the appropriate development of the mammalian nervous system.21,22.”

• cites [21] Bruni, 2007, Heterogeneity within a large kindred with frontotemporal dementia: a novel progranulin mutation, Neurology sourceNot checked — no full text of the source
• cites [22] Bulut-Karslioglu, 2016, Inhibition of mTOR induces a paused pluripotent state, Nature sourceCould not verify

  The Methods section describes an apoptosis assay in embryonic stem cells, and Extended Data Figures 2 and 4 discuss apoptosis and an autophagy/lysosomal inhibitor in blastocysts. Neither passage addresses whether lysosomes are important in apoptosis or whether apoptosis is required for mammalian nervous-system development; searches for those connections found no supporting passage in our copy. Page numbers were not provided. (LLM, conf=0.76)

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Damaged organelles are cleared by lysosomes through dedicated machinery (mitophagy, ER-phagy, etc).

“Similarly, damaged organelles are cleared by lysosomes through dedicated machinery (mitophagy, ER-phagy, etc).50”

• cites [50] Do, 2011, Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinson’s disease, PLoS Genet sourceCould not verify

  The Discussion describes LIMP-2 directing an enzyme to the lysosome, but does not discuss clearance of damaged organelles. Searches for mitophagy, ER-phagy, and lysosomal clearance of damaged mitochondria or endoplasmic reticulum found no passage addressing the claim; page numbers were unavailable in our copy. (LLM, conf=0.76)

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Kufor-Rakeb syndrome is an autosomal recessive early-onset form of Parkinson's disease caused by mutations in the lysosomal ATPase protein, ATP13A2.

“A striking example of this overlap is Kufor-Rakeb syndrome, an autosomal recessive early-onset form of Parkinson’s disease caused by mutations in the lysosomal ATPase protein, ATP13A2.”

• cites [62] Geisler, 2010, The PINK1/Parkin-mediated mitophagy is compromised by PD-associated mutations, Autophagy sourceCould not verify

  The Introduction and Discussion discuss Parkinson’s disease mutations in PINK1 and Parkin, not Kufor-Rakeb syndrome. Searches for “Kufor-Rakeb syndrome” and “ATP13A2 lysosomal ATPase” found no passage addressing the claimed syndrome, inheritance, or cause; page numbers were not available in our copy. (LLM, conf=0.76)

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• cites [63] Ghavami, 2014, Autophagy and apoptosis dysfunction in neurodegenerative disorders, Prog. Neurobiol. sourceCould not verify

  Section 10 (Parkinson’s disease; page unavailable) discusses genetic forms of Parkinson’s disease, particularly LRRK2, but does not address Kufor-Rakeb syndrome. Searches for Kufor-Rakeb, ATP13A2, and PARK9 found no passage stating its inheritance, onset, or proposed cause. (LLM, conf=0.75)

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Animal models with defective lysosomal exocytosis (VAMP7 mice) or defective lysosomal protease activity (Cathepsin D mutant mice) have mild to moderate demyelination.

“and animal models with defective lysosomal exocytosis (VAMP7 mice) or defective lysosomal protease activity (Cathepsin D mutant mice) have mild to moderate demyelination.40–42”

• cites [40] Cuervo, 1996, A receptor for the selective uptake and degradation of proteins by lysosomes, Science sourceNot checked — no full text of the source
• cites [41] Cuervo, 2000, Age-related Decline in Chaperone-mediated Autophagy, J. Biol. Chem. sourceCould not verify

  The Results discuss lysosomes from young and old rat livers, and the Experimental Procedures mention a cathepsin D antibody; neither addresses mutant mice or demyelination. Searches for VAMP7, lysosomal exocytosis, cathepsin D mutant mice, and demyelination found no passage supporting the claim. Page numbers were unavailable in our copy. (LLM, conf=0.78)

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• cites [42] Cuervo, 2004, Impaired degradation of mutant α-synuclein by chaperone-mediated autophagy, Science sourceNot checked — no full text of the source

Certain disease-associated proteins have been shown to impair lysosomal acidification.

“Moreover, certain disease-associated proteins have been shown to impair lysosomal acidification.”

• cites [60] Geier, 2019, Rare variants in the neuronal ceroid lipofuscinosis gene MFSD8 are candidate risk factors for frontotemporal dementia, Acta Neuropathol. sourcePartly supported

  The Results section (“Lysosomal malfunctioning in MFSD8 rare variant carriers”; page not available) reports reduced lysosomal protein degradation in cells carrying FTLD-associated MFSD8 variants. It does not report a measurement or finding that these variants impair lysosomal acidification; searches for acidification and lysosomal pH returned only degradation-related passages. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

Some PD risk genes, such as ASAH1 and GLB1, have only been identified in a single GWAS study of PD risk, with no mechanistic or confirmatory follow up.

“In contrast to the genes above, which have stronger links both genetically and mechanistically to PD, some PD risk genes, such as ASAH1 and GLB1, have only been identified in a single GWAS study of PD risk, with no mechanistic or confirmatory follow up.7”

• cites [7] Alquezar, 2020, Heavy metals contaminating the environment of a progressive supranuclear palsy cluster induce tau accumulation and cell death in cultured neurons, Sci. Rep. 2020 10 sourceCould not verify

  The Introduction discusses genetic associations with progressive supranuclear palsy and environmental exposure, not ASAH1 or GLB1 as Parkinson’s disease risk genes. Searches for those genes and for a single PD GWAS with no follow-up found no passage addressing the claim in our copy. The indexed passages have no page numbers. (LLM, conf=0.76)

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NCL-associated genes typically encode proteins involved in proteolysis, lipid catabolism, or have unidentified lysosomal roles.

“The genes associated with NCLs are typically in proteins involved in proteolysis (such as the cathepsin proteases), lipid catabolism, or have unidentified roles in the lysosome (e.g., MSFD8).118”

• cites [118] Nixon, 2020, The aging lysosome: An essential catalyst for late-onset neurodegenerative diseases, Biochim Biophys. Acta Proteins Prote sourceCould not verify

  The Introduction (“Aging lysosomes – a critical precondition for late-age onset neurodegenerative diseases”; page unavailable) links progranulin mutations to childhood NCL, but does not classify NCL-associated genes by protein function. Searches for MFSD8, proteolysis, lipid catabolism, and NCL-associated genes found no passage in our copy stating the claimed categories. (LLM, conf=0.73)

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Lysosomal membranes are particularly enriched in sphingolipids.

“Lysosomal membranes are particularly enriched in sphingolipids.”

• cites [94] Kuo, 2022, Mutant glucocerebrosidase impairs α-synuclein degradation by blockade of chaperone-mediated autophagy, Sci. Adv. sourceCould not verify

  The Results sections on lysosomal trafficking and GCase localization discuss lysosomal membranes but do not describe their sphingolipid content. Searches for “sphingolipid” and lysosomal membrane lipid composition found no passage supporting the claimed enrichment; page numbers were unavailable in our copy. (LLM, conf=0.72)

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Heterozygous progranulin (GRN) mutations are associated with FTD with TDP-43 Type A pathology.

“Heterozygous progranulin (GRN) mutations are associated with FTD with TDP-43 Type A pathology.79,111”

• cites [79] Ibata, 2019, Activity-dependent secretion of synaptic organizer Cbln1 from lysosomes in granule cell axons, Neuron sourceCould not verify

  The supplied Results and Discussion passages address Cbln1 secretion and cerebellar synapse formation, not progranulin mutations or FTD pathology. Searches for heterozygous GRN mutations, frontotemporal dementia, and TDP-43 Type A pathology found no passage in our copy addressing the claimed association. (LLM, conf=0.76)

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• cites [111] Mindell, 2012, Lysosomal acidification mechanisms, Annu Rev. Physiol. sourceNot checked — no full text of the source

Reducing GlcCer levels by inhibiting GlcCer synthase reduces alpha-synuclein aggregation in mouse models of GD or PD.

“Reducing GlcCer levels by inhibiting GlcCer synthase reduces alpha-synuclein aggregation in mouse models of GD or PD.96,97”

• cites [96] Lee, 2015, Presenilin 1 Maintains Lysosomal Ca(2+) Homeostasis via TRPML1 by Regulating vATPase-Mediated Lysosome Acidification, Cell Rep. sourceCould not verify

  The Introduction discusses lysosomal dysfunction in Parkinson’s disease and the therapeutic potential of lysosome modulation, but does not address GlcCer synthase inhibition or alpha-synuclein aggregation in GD or PD mouse models. Searches for those specific terms in our copy found no passage reporting the claimed result; page numbers were not provided. (LLM, conf=0.76)

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• cites [97] Lee, 2022, Faulty autolysosome acidification in Alzheimer’s disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques, Nat. Neurosci. 2022 25 sourceCould not verify

  Our copy discusses autolysosome acidification and Aβ accumulation in Alzheimer’s disease mouse models (AL acidification deficiency arises before β-amyloid deposits). A reference mentions glucosylceramide in Niemann–Pick type C disease, but the passages found do not address GlcCer synthase inhibition or reduced alpha-synuclein aggregation in Gaucher disease or Parkinson’s disease mouse models (searched: GlcCer synthase, glucosylceramide synthase, synuclein). (LLM, conf=0.76)

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Mutations in cathepsins D and F lead to NCL.

“Mutations in several of the cathepsins lead to NCL (D and F), and others have also been identified as risk factors for neurodegenerative disease (B, D, and F).88,122,123”

• cites [88] Kobayashi, 2021, Lysosomes and signaling pathways for maintenance of quiescence in adult neural stem cells, FEBS J. sourceCould not verify

  The 'Lysosomes in quiescent NSCs' section discusses lysosomal activity and autophagy, but does not address cathepsin D or F mutations or NCL. Searches for those terms and for cathepsins in neurodegenerative disease found no passage in our copy supporting the claim; no page numbers were provided. (LLM, conf=0.72)

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• cites [122] Orenstein, 2013, Interplay of LRRK2 with chaperone-mediated autophagy, Nat. Neurosci. 2013 16 sourceCould not verify

  The Discussion addresses LRRK2 mutations and Parkinson’s disease, not cathepsin D or F mutations and NCL. A search for cathepsins in our copy found a reference to cathepsin A, but no passage supporting the attributed claim. (LLM, conf=0.76)

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• cites [123] Ormeño, 2020, Chaperone mediated autophagy degrades TDP-43 protein and is affected by TDP-43 aggregation, Front Mol. Neurosci. sourceCould not verify

  The Discussion (page unavailable) concerns TDP-43 aggregation and chaperone-mediated autophagy, not mutations in cathepsins D or F. Searches for cathepsin D and F mutations, NCL, and neuronal ceroid lipofuscinosis found no passage in our copy addressing the claim. (LLM, conf=0.77)

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Infants with Krabbe disease develop alpha-synuclein inclusions that exhibit prion-like spread similar to the alpha-synuclein of PD.

“In addition to accumulating glycosphingolipids, infants with Krabbe disease develop alpha-synuclein inclusions that exhibit prion-like spread similar to the alpha-synuclein of PD.104”

• cites [104] Malpartida, 2021, Mitochondrial dysfunction and mitophagy in parkinson’s disease: from mechanism to therapy, Trends Biochem Sci. sourceCould not verify

  The α-synuclein section discusses aggregation and Lewy bodies in Parkinson’s disease, but does not address infants with Krabbe disease or prion-like spread. Searches for Krabbe disease, glycosphingolipids, and prion-like spread found no passage supporting the attributed claim. (LLM, conf=0.72)

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The type of inclusion in FTD correlates well with brain regions involved, clinical symptomology, and the overall disease course of FTD.

“The type of inclusion in FTD correlates well with brain regions involved, clinical symptomology, and the overall disease course of FTD.78”

• cites [78] Hwang, 2023, Tuberous sclerosis complex is associated with a novel human tauopathy, Acta Neuropathol. sourceCould not verify

  The Results section maps tau inclusions across brain regions in three people with TSC, but does not compare inclusion types in FTD or correlate them with symptoms or disease course (page unavailable). The Discussion says a progressive FTD-like syndrome with matching autopsy findings would be needed to classify TSC tauopathy as FTLD-tau. Searches for inclusion type, clinical phenotype, regional distribution, and disease course found no passage establishing the claimed correlations. (LLM, conf=0.72)

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The GBA substrates glucosylceramide (GlcCer) and its deacetylated derivative glucosylsphingosine (GlcSph) enhance nucleation of alpha-synuclein aggregates.

“The GBA substrates glucosylceramide (GlcCer) and its deacetylated derivative glucosylsphingosine (GlcSph) enhance nucleation of alpha-synuclein aggregates.”

• cites [96] Lee, 2015, Presenilin 1 Maintains Lysosomal Ca(2+) Homeostasis via TRPML1 by Regulating vATPase-Mediated Lysosome Acidification, Cell Rep. sourceCould not verify

  The Introduction discusses presenilin 1, lysosomal function, and amyloid-beta, not whether GBA substrates promote alpha-synuclein aggregation. Searches for glucosylceramide, glucosylsphingosine, GlcCer, GlcSph, and aggregate nucleation found no passage in our copy addressing the claim; a synuclein-related reference does not establish it. (LLM, conf=0.75)

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• cites [97] Lee, 2022, Faulty autolysosome acidification in Alzheimer’s disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques, Nat. Neurosci. 2022 25 sourceCould not verify

  The paper’s discussion of lysosomal storage disorders mentions intracellular synuclein accumulation, and its References list a study concerning glucosylceramide and endolysosomal function. Neither passage addresses whether glucosylceramide or glucosylsphingosine enhances alpha-synuclein nucleation. Searches for GlcSph, GBA substrates, and alpha-synuclein nucleation found no supporting passage in our copy. (LLM, conf=0.76)

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GRN mutations exhibit full penetrance for disease by age 80.

“GRN mutations exhibit full penetrance for disease by age 80.112,113”

• cites [112] Mohan, 2021, Processing of progranulin into granulins involves multiple lysosomal proteases and is affected in frontotemporal lobar degeneration, Mol. Neurodegener. sourcePartly supported

  The Background (page unavailable) says that progranulin haploinsufficiency leads to adult-onset FTLD, supporting the link between GRN mutations and disease. It does not state that penetrance is complete by age 80; searches for penetrance and that age found no such passage. (LLM, conf=0.85)

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• cites [113] Mutka, 2010, Murine cathepsin D deficiency is associated with dysmyelination/myelin disruption and accumulation of cholesteryl esters in the brain, J. Neurochem. sourceCould not verify

  The paper’s Abstract (p. 2) concerns CTSD deficiency and myelin changes in mice, not GRN mutations. Searches for GRN, progranulin, penetrance, and age 80 found no passage addressing the claimed disease penetrance. (LLM, conf=0.76)

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GWAS identified the rs979812 locus in GALC as increasing PD risk.

“GWAS identified the rs979812 locus in GALC as increasing PD risk.105,106”

• cites [105] Mancini, 2023, Lysosomal glucose sensing and glycophagy in metabolism, Trends Endocrinol. Metab. sourceCould not verify

  The passages returned from the References section concern glycogen metabolism and lysosomal disease, not a Parkinson’s disease GWAS. Searches of our copy for rs979812, GALC, and Parkinson found no passage linking that locus to increased PD risk. (LLM, conf=0.76)

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• cites [106] Martínez-Cerdeño, 2017, Dendrite and spine modifications in autism and related neurodevelopmental disorders in patients and animal models, Dev. Neurobiol. sourceCould not verify

  The 'Other autism related genes' section discusses SNP associations with autism in MARK1, not the rs979812 locus in GALC or Parkinson’s disease risk. Searches for rs979812, GALC, and Parkinson’s disease found no passage in our copy addressing the claimed GWAS finding; page numbers were unavailable. (LLM, conf=0.75)

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Biallelic loss-of-function mutations in GRN cause juvenile-onset neuronal ceroid lipofuscinosis (NCL).

“Subsequently, rare families with biallelic loss of function mutations in GRN were identified, and affected individuals were found to have a juvenile-onset neuronal ceroid lipofuscinosis (NCL).114–116”

• cites [114] Nalls, 2014, Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease, Nat. Genet. 2014 46 sourceCould not verify

  The Abstract and Expression and Methylation Methods passages describe Parkinson’s disease risk loci and gene-expression analyses, not GRN-related NCL. Searches for biallelic GRN loss of function and juvenile-onset neuronal ceroid lipofuscinosis returned no passage addressing the claim. (LLM, conf=0.75)

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• cites [115] Narendra, 2010, PINK1 is selectively stabilized on impaired mitochondria to activate Parkin, PLoS Biol. sourceCould not verify

  The Discussion addresses recessive PINK1 and Parkin mutations in early-onset Parkinson disease, not GRN mutations or neuronal ceroid lipofuscinosis. Searches for GRN, biallelic loss of function, and juvenile-onset neuronal ceroid lipofuscinosis found no passage addressing the claim in our copy. (LLM, conf=0.78)

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• cites [116] Neumann, 2009, Glucocerebrosidase mutations in clinical and pathologically proven Parkinson’s disease, Brain sourceCould not verify

  The Introduction discusses GBA mutations and Gaucher disease, while the Mutations in GBA section reports GBA variants; neither addresses GRN. Searches for biallelic GRN loss of function and juvenile-onset neuronal ceroid lipofuscinosis found no relevant passage in our copy. Page numbers were not available. (LLM, conf=0.78)

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This led to the identification of some of the earliest disease-associated genes, including APP, PS1 and PS2 in AD, SNCA and LRRK2 in PD and MAPT and GRN in FTD.

“This subsequently led to the identification of some of the earliest disease-associated genes, including APP, PS1 and PS2 in AD, SNCA and LRRK2 in PD and MAPT and GRN in FTD.79–87”

• cites [79] Ibata, 2019, Activity-dependent secretion of synaptic organizer Cbln1 from lysosomes in granule cell axons, Neuron sourceCould not verify

  The supplied passages and searches for APP, PS1, PS2, SNCA, LRRK2, MAPT, GRN, and early disease-gene identification found no passage addressing the claim. The paper instead discusses activity-dependent Cbln1 release from granule cells (Abstract; page unavailable). (LLM, conf=0.78)

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• cites [80] Jardim, 2010, Clinical aspects of neuropathic lysosomal storage disorders, J. Inherit. Metab. Dis. sourceNot checked — no full text of the source
• cites [81] Jiao, 2023, TMEM106B aggregation in neurodegenerative diseases: linking genetics to function, Mol. Neurodegener. sourcePartly supported

  The section ‘Other risk factors interact with TMEM106B pathology’ says GRN loss-of-function mutations cause familial FTD, and the figure caption identifies MAPT mutations as a cause of familial frontotemporal dementia and parkinsonism (no page numbers supplied). Our copy does not substantiate the listed AD or PD genes or the claim that these were among the earliest disease-associated genes identified. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites [82] Kabuta, 2008, Aberrant Interaction between Parkinson Disease-associated Mutant UCH-L1 and the Lysosomal Receptor for Chaperone-mediated Autophagy, J. Biol. Chem. sourcePartly supported

  The paper’s introductory passage reports that mutations and copy-number increases in the α-synuclein gene (SNCA) are linked to familial Parkinson disease. It does not address the listed AD or FTD genes, LRRK2, or the claim that these were among the earliest disease-associated genes identified. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [83] Karch, 2017, Autophagic cell death is dependent on lysosomal membrane permeability through bax and bak, Elife sourceCould not verify

  The Results and Materials and methods passages concern Bax/Bak-mediated cell death, not the identification of genes associated with AD, PD, or FTD. Searches for APP, PS1, PS2, SNCA, LRRK2, MAPT, and GRN, and for the three diseases, found no passage addressing the claim. (LLM, conf=0.78)

  Experimental — accuracy not yet measured
• cites [84] Kaushik, 2021, Autophagy and the hallmarks of aging, Ageing Res Rev. sourceCould not verify

  The passages from “Autophagy activators as novel geroprotectors” discuss tauopathy models and autophagy treatments, not the discovery of disease-associated genes. Searches for the listed genes and for early genetic discoveries in AD, PD, and FTD found no passage in our copy that addresses the claim; a References entry mentions APP/PS1 mice but not gene identification. No page numbers were provided for these passages. (LLM, conf=0.74)

  Experimental — accuracy not yet measured
• cites [85] Kavčič, 2017, Lysosomes in programmed cell death pathways: from initiators to amplifiers, Biol. Chem. sourceNot checked — no full text of the source
• cites [86] Kirchner, 2019, Proteome-wide analysis of chaperone-mediated autophagy targeting motifs, PLoS Biol. sourcePartly supported

  The Results section (‘Position of motifs within proteins’; page unavailable) links α-synuclein to Parkinson disease pathology, supporting only a narrow part of the PD association. It does not describe the early identification of disease-associated genes or establish the listed AD and FTD gene associations; the LRRK2 mention is in a reference about autophagy. (LLM, conf=0.72)

  Experimental — accuracy not yet measured
• cites [87] Knopman, 2021, Alzheimer disease, Nat. Rev. Dis. Prim. 2021 7 sourcePartly supported

  The genetic-risk discussion (labelled Abstract in our copy; page unavailable) identifies APP, PSEN1 and PSEN2—the genes referred to as APP, PS1 and PS2—as associated with dominantly inherited Alzheimer disease. It does not establish that they were among the earliest genes identified or that the preceding development led to their identification. As an Alzheimer disease review, it is not evidence for the PD and FTD gene examples, which appear to be covered by other citations in the range. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

Microglia in the substantia nigra have a much higher lysosomal content compared to other basal ganglia nuclei.

“Specifically, microglia in the substantia nigra have a much higher lysosomal content compared to other basal ganglia nuclei.109”

• cites [109] Melentijevic, 2017, C. elegans neurons jettison protein aggregates and mitochondria under neurotoxic stress, Nature 2017 542 sourceCould not verify

  The Extended Data passages describe lysosomes in C. elegans touch neurons and exophers, not microglia. Searches for substantia nigra, basal ganglia, and comparative microglial lysosomal content found no passage addressing the claim. (LLM, conf=0.78)

  Experimental — accuracy not yet measured

Many LSDs can feature neurodevelopmental symptoms, such as autism and intellectual disability.

“Many LSDs can feature neurodevelopmental symptoms, such as autism and intellectual disability.67–69”

• cites [67] Guo, 2018, Cathepsin D deficiency delays central nervous system myelination by inhibiting proteolipid protein trafficking from late endosome/lysosome to plasma membrane, Exp. Mol. Med sourcePartly supported

  The Introduction links cathepsin D mutations to neurological disease in human infants and to some lysosomal storage disorders; the Results report delayed CNS myelination in cathepsin D–deficient mice. These passages support a developmental neurological connection, but do not establish that many lysosomal storage disorders feature autism or intellectual disability. (LLM, conf=0.80)

  Experimental — accuracy not yet measured
• cites [68] Hansen, 2018, Autophagy as a promoter of longevity: insights from model organisms, Nat. Rev. Mol. Cell Biol. sourceCould not verify

  The ‘Genetic links of autophagy to ageing’ section discusses lysosomal dysfunction and neurodegenerative diseases, while ‘Nervous system’ discusses age-related memory impairment. Neither addresses whether many lysosomal storage disorders feature autism or intellectual disability. Searches for lysosomal storage disorders, autism, and intellectual disability found no passage supporting that point; page numbers were not available in our copy. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [69] Hatton, 2022, Prion-like α-synuclein pathology in the brain of infants with Krabbe disease, Brain sourcePartly supported

  The Materials and methods table (page not available) records developmental delay in three infants with Krabbe disease, supporting a neurodevelopmental symptom in one lysosomal storage disease. The paper does not establish that many such diseases feature these symptoms, or report autism or intellectual disability. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

SCARB2 has been identified in several PD risk genome-wide association studies.

“SCARB2 has been identified in several PD risk genome-wide association studies (GWAS).100–103”

• cites [100] Liao, 2019, RNA Granules Hitchhike on Lysosomes for Long-Distance Transport, Using Annexin A11 as a Molecular Tether, Cell sourceCould not verify

  The Introduction discusses genetic links to ALS/FTD, not SCARB2 or Parkinson’s disease risk. Searches for SCARB2, PD risk, and genome-wide association studies found no passage in our copy addressing the claim; the occurrence of “Parkinson” in the References is an author’s surname. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [101] Logan, 2021, Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic, Cell sourceCould not verify

  The Introduction discusses GBA-linked Parkinson’s disease, and the References list a Parkinson’s disease GWAS meta-analysis, but neither passage says that SCARB2 was identified in several PD risk GWAS. Searches for SCARB2 and LIMP-2 found no passage addressing that claim in our copy. (LLM, conf=0.72)

  Experimental — accuracy not yet measured
• cites [102] Ma, 2019, SQSTM1/p62: a potential target for neurodegenerative disease, ACS Chem. Neurosci. sourceCould not verify

  The section “Regulation of p62 in Parkinson’s Disease (PD)” discusses genetic factors in PD, including parkin, PINK1 and LRRK2, but does not identify SCARB2 as a PD risk locus. Searches of our copy for SCARB2 and for PD genome-wide association studies found no passage addressing the claimed finding; page numbers were not available. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [103] Maday, 2014, Axonal transport: cargo-specific mechanisms of motility and regulation, Neuron sourceCould not verify

  The retrieved passages from the paper’s References section concern axonal transport and other neurological conditions, not SCARB2 or Parkinson’s disease risk GWAS. Searches for SCARB2, GWAS, and the claimed association found no passage in our copy addressing it. (LLM, conf=0.73)

  Experimental — accuracy not yet measured

In C. elegans, granulins accumulate with age.

“In C. elegans, granulins accumulate with age, and multi-granulin fragments accumulate in diseased brain regions from patients with GRN-FTD and AD.133”

• cites [133] Radke, 2015, Human NCL neuropathology, Biochim. Et. Biophys. Acta (BBA) Mol. Basis Dis. sourceCould not verify

  The Electron microscopy section discusses accumulation of NCL-associated proteins, and Table 3 mentions GRN-associated pathology, but neither addresses granulin accumulation in C. elegans. Searches for C. elegans, age-related granulin accumulation, and multi-granulin fragments found no passage supporting the cited sentence. Page numbers were not available in our copy. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

Tau acetylation impairs tau clearance through CMA by reducing entry into the lysosome and proteolysis by the lysosome.

“Tau acetylation contributes to tau pathology via multiple potential mechanisms: promoting tau fibrillation146 and impairing tau clearance through CMA both by reducing entry into the lysosome and proteolysis by the lysosome.147”

• cites [147] Stavoe, 2019, Autophagy in neurons, Annu Rev. Cell Dev. Biol. sourceCould not verify

  The Introduction describes chaperone-mediated autophagy as a neuronal protein-degradation pathway, and “Autophagy in Disease” says defects in that pathway may contribute to neurodegeneration. Neither passage addresses tau acetylation, tau entry into lysosomes, or its lysosomal proteolysis; searches for those terms found no supporting passage in our copy. Page numbers were not available. (LLM, conf=0.75)

  Experimental — accuracy not yet measured

Alzheimer's pathology has been observed in postmortem tissues from several NCL patients.

“As an example, cathepsin D knockout mice accumulate Ab in addition to lipofuscin, and Alzheimer’s pathology has been observed in postmortem tissues from several NCL patients.125–127”

• cites [125] Pará, 2020, Neuropathophysiology of lysosomal storage diseases: synaptic dysfunction as a starting point for disease progression, J. Clin. Med sourceCould not verify

  The Introduction (page unavailable) links amyloid-β and tau to CNS pathology in multiple lysosomal storage diseases, but does not identify postmortem NCL patients. The NCL passages in sections 2 and 4 discuss animal models and patient-derived cells, not Alzheimer’s pathology in postmortem tissue. Searches for postmortem NCL tissue, amyloid, and Alzheimer’s pathology found no passage establishing the claim. (LLM, conf=0.72)

  Experimental — accuracy not yet measured
• cites [126] Parenti, 2021, The rapidly evolving view of lysosomal storage diseases, EMBO Mol. Med sourceCould not verify

  The Secondary storage section links lysosomal storage diseases broadly to proteins associated with Alzheimer’s disease, but does not report Alzheimer’s pathology in postmortem tissue from NCL patients. Searches for postmortem NCL tissue and Alzheimer’s pathology found no passage addressing that observation in our copy. (LLM, conf=0.73)

  Experimental — accuracy not yet measured
• cites [127] Park, 2015, The role of ATP13A2 in Parkinson’s disease: clinical phenotypes and molecular mechanisms, Mov. Disord. sourceNot checked — no full text of the source

Mutations in ATP6V1A were identified in patients with encephalopathies, moderate intellectual disability, and epilepsy.

“Mutations in ATP6V1A, which encodes a subunit of the vATPase, were identified in patients with encephalopathies as well as moderate intellectual disability and epilepsy.156”

• cites [156] Wang, 2021, Transformative network modeling of multi-omics data reveals detailed circuits, key regulators, and potential therapeutics for alzheimer’s disease, Neuron sourcePartly supported

  The References list Fassio et al. (2018) as a study of ATP6V1A mutations causing developmental encephalopathy with epilepsy, and the Discussion describes effects of two such mutations in rat neurons. Our copy does not state that patients had moderate intellectual disability, nor does it itself report identifying mutations in patients. (LLM, conf=0.77)

  Experimental — accuracy not yet measured

NCL5 encodes the bis(monacylglycero)phosphate (BMP) synthase.

“In contrast to most of the NCL genes, which appear to disrupt protein homeostasis, NCL5 was very recently identified to encode the bis(monacylglycero)phosphate (BMP) synthase.136”

• cites [136] Robak, 2017, Excessive burden of lysosomal storage disorder gene variants in Parkinson’s disease, Brain sourceCould not verify

  The Discussion table lists CLN5 as a neuronal ceroid lipofuscinosis gene, and Variant selection says no CLN5 variants passed the study’s missingness criterion. Neither passage identifies its protein product or says it synthesizes BMP; searches for BMP synthase and CLN5 function found no such statement in our copy. (LLM, conf=0.75)

  Experimental — accuracy not yet measured

Cathepsins have preferred cleavage sites and differentially cleave neurodegenerative disease proteins such as tau, TDP-43, and alpha-synuclein.

“Even within the three cathepsin families, cathepsins each have preferred cleavage sites which are apparent in how they differentially cleave neurodegenerative disease proteins such as tau, TDP-43, and alpha-synuclein.124”

• cites [124] Padamsey, 2017, Activity-dependent exocytosis of lysosomes regulates the structural plasticity of dendritic spines, Neuron sourceCould not verify

  The Results section, “Lysosomal Fusion Results in the Release of Cathepsin B” (page unavailable), identifies cathepsins as proteases, and “Cathepsin B Release Activates MMP-9” describes Cathepsin B cleaving TIMP-1. Our copy does not address preferred cleavage sites or differential cleavage of tau, TDP-43, and alpha-synuclein (searched for those proteins and cleavage specificity). (LLM, conf=0.75)

  Experimental — accuracy not yet measured

Tubers isolated from infants with TSC1 mutations demonstrate hyperphosphorylated tau.

“Tubers isolated from infants with TSC1 mutations demonstrate hyperphosphorylated tau and thus it is recognized as a “juvenile tauopathy.”139”

• cites [139] Sampognaro, 2023, Mutations in α-synuclein, TDP-43 and tau prolong protein half-life through diminished degradation by lysosomal proteases, Mol. Neurodegener. sourceCould not verify

  The Results (Tau; page unavailable) examine lysosomal cleavage of tau, not tubers from infants. The References list a study on TSC1 loss and tauopathy, but our copy does not report hyperphosphorylated tau in infant tubers or describe TSC1-associated tubers as a juvenile tauopathy. Searches for infant tubers, TSC1, hyperphosphorylated tau, and juvenile tauopathy found no passage establishing the claim. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

Reducing tau acetylation restores its degradation through CMA.

“Reducing tau acetylation restores its degradation through CMA (Figure 5).90,147”

• cites [90] Korvatska, 2013, Altered splicing of ATP6AP2causes X-linked parkinsonism with spasticity (XPDS), Hum. Mol. Genet sourceCould not verify

  The Results describe impaired autophagy and lysosomal clearance with ATP6AP2 deficiency, and the Discussion notes pathological tau deposits in XPDS brain (pages not provided). Searches for tau acetylation, deacetylation, and chaperone-mediated autophagy found no passage saying that reducing tau acetylation restores its degradation through CMA. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [147] Stavoe, 2019, Autophagy in neurons, Annu Rev. Cell Dev. Biol. sourceCould not verify

  The Introduction (page not available) mentions chaperone-mediated autophagy as a neuronal protein-degradation pathway, but does not discuss tau. Searches for tau, acetylation, and CMA found no passage stating that reducing tau acetylation restores its degradation through CMA. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

Cathepsins B, D, and F are risk factors for neurodegenerative disease.

“Mutations in several of the cathepsins lead to NCL (D and F), and others have also been identified as risk factors for neurodegenerative disease (B, D, and F).88,122,123”

• cites [88] Kobayashi, 2021, Lysosomes and signaling pathways for maintenance of quiescence in adult neural stem cells, FEBS J. sourceCould not verify

  The section “The lysosome: a digestive organelle and a hub of nutrition signaling” describes lysosomal degradation, and “Lysosomes in quiescent NSCs” discusses autophagy and neural stem cells; neither identifies cathepsins B, D, or F as neurodegenerative-disease risk factors. Searches for cathepsin, neuronal ceroid lipofuscinosis, and the risk-factor claim found no passage addressing that association. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [122] Orenstein, 2013, Interplay of LRRK2 with chaperone-mediated autophagy, Nat. Neurosci. 2013 16 sourceCould not verify

  The Discussion (page unavailable) addresses LRRK2 and α-synuclein in Parkinson’s disease, not cathepsins B, D, or F as neurodegenerative-disease risk factors. A search for “cathepsin” found only a References entry concerning cathepsin A; searches for the named cathepsins and NCL found no supporting passage in our copy. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [123] Ormeño, 2020, Chaperone mediated autophagy degrades TDP-43 protein and is affected by TDP-43 aggregation, Front Mol. Neurosci. sourceCould not verify

  The Introduction and Discussion discuss autophagy, TDP-43, and neurodegeneration, but do not identify cathepsins B, D, or F as disease risk factors. Searches for those cathepsins and for NCL mutations found only a reference to unspecified cathepsin-dependent activity, not the attributed claim. Page numbers are unavailable in our copy. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

Individual granulins seemingly inhibit CTSD activity.

“In contrast, individual granulins seemingly inhibit CTSD activity.133”

• cites [133] Radke, 2015, Human NCL neuropathology, Biochim. Et. Biophys. Acta (BBA) Mol. Basis Dis. sourceCould not verify

  The Light microscopy section discusses cathepsin D deficiency in CLN10, while Table 3 lists CTSD and GRN separately in NCL pathology. Neither passage addresses whether individual granulins inhibit CTSD activity. Searches for that interaction and for progranulin-related enzyme inhibition found no supporting passage in our copy. (LLM, conf=0.74)

  Experimental — accuracy not yet measured

Mutant glucocerebrosidase A (GBA1) can be mis-trafficked to the lysosomal surface instead of the lysosomal lumen.

“Second, it was recently shown that mutant glucocerebrosidase A (the protein encoded by GBA1) can be mis-trafficked to the lysosomal surface instead of the lysosomal lumen. There, it binds to and interferes with normal LAMP2A function, impeding processing of CMA client proteins, particularly alpha-synuclein.99”

• cites [99] Li, 2023, Disease-associated patterns of acetylation stabilize tau fibril formation, Structure sourceCould not verify

  The Discussion describes how lysine acetylation affects tau fibril formation, not glucocerebrosidase trafficking. Searches for GBA1, the lysosomal surface and lumen, LAMP2A, and chaperone-mediated autophagy found no passage addressing the attributed claim. Page numbers are not available in our copy. (LLM, conf=0.78)

  Experimental — accuracy not yet measured

Multi-granulin fragments accumulate in diseased brain regions from patients with GRN-FTD and AD.

“In C. elegans, granulins accumulate with age, and multi-granulin fragments accumulate in diseased brain regions from patients with GRN-FTD and AD.133”

• cites [133] Radke, 2015, Human NCL neuropathology, Biochim. Et. Biophys. Acta (BBA) Mol. Basis Dis. sourceCould not verify

  The Electron microscopy section discusses accumulation of NCL-associated proteins, while Table 3 lists GRN-associated lipopigments in sweat gland cells. Neither addresses multi-granulin fragments in GRN-FTD or AD brain regions; searches for those fragments and diseases found no supporting passage in our copy. The passages do not specify page numbers. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

At least five other PD-associated genes (LRRK2, UCHL2, VCP35, DJ-1, and SNCA) affect CMA.

“At least five other genes that are associated with PD (but not LSDs) also affect CMA: LRRK2, UCHL2, VCP35, DJ-1, and SNCA, which encodes alpha-synuclein.149–153”

• cites [149] Stoka, 2016, Lysosomal cathepsins and their regulation in aging and neurodegeneration, Ageing Res Rev. sourceCould not verify

  Section 4 (Autophagy; page unavailable) identifies CMA as an autophagy pathway, and §6.3 (Parkinson’s disease; page unavailable) discusses α-synuclein in PD. Neither passage says that SNCA or the other four named genes affect CMA; searches for those genes and chaperone-mediated autophagy found no such link in our copy. (LLM, conf=0.74)

  Experimental — accuracy not yet measured
• cites [150] Suire, 2020, Cathepsin D regulates cerebral Aβ42/40 ratios via differential degradation of Aβ42 and Aβ40, Alzheimers Res Ther. sourceCould not verify

  The Discussion addresses cathepsin D and amyloid-β in Alzheimer’s disease, while the References include work on lysosomal processing; neither addresses whether the five named Parkinson’s disease genes affect CMA. Searches for the gene names and for chaperone-mediated autophagy found no passage supporting the attributed claim. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [151] Sun, 2020, Lysosome activity is modulated by multiple longevity pathways and is important for lifespan extension in C. Elegans, Elife sourceCould not verify

  The Results sections on lysosome activity and aggregate clearance in C. elegans do not address whether the listed Parkinson’s disease-associated genes affect chaperone-mediated autophagy. Searches for the five gene names, CMA, Parkinson’s disease, and alpha-synuclein found no passage in our copy that speaks to the claim. (LLM, conf=0.75)

  Experimental — accuracy not yet measured
• cites [152] Tang, 2015, VPS35 in dopamine neurons is required for endosome-to-golgi retrieval of Lamp2a, a receptor of chaperone-mediated autophagy that is critical for α-synuclein degradation and prevention of pathogenesis of parkinson’s disease, J. Neurosci. sourceNot checked — no full text of the source
• cites [153] Trajkovic, 2006, Neuron to glia signaling triggers myelin membrane exocytosis from endosomal storage sites, J. Cell Biol. sourceCould not verify

  The Results section discusses neuronal regulation of myelin proteolipid protein trafficking, not Parkinson’s disease genes or chaperone-mediated autophagy. Searches for the listed genes, CMA, and alpha-synuclein found no passage addressing the claim in our copy; page numbers were not available. (LLM, conf=0.78)

  Experimental — accuracy not yet measured

TSC1 mutations increase the risk of FTD with tau accumulation.

“In recent years, we showed that TSC1 mutations also increase the risk of FTD with tau accumulation.90,140”

• cites [90] Korvatska, 2013, Altered splicing of ATP6AP2causes X-linked parkinsonism with spasticity (XPDS), Hum. Mol. Genet sourceCould not verify

  The Discussion describes an ATP6AP2 mutation causing X-linked parkinsonism with spasticity and reports tau deposits in an XPDS brain. A search for TSC1 mutations and frontotemporal dementia found no passage in our copy addressing whether TSC1 increases the risk of FTD with tau accumulation; page numbers were not available. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [140] Sardi, 2017, Glucosylceramide synthase inhibition alleviates aberrations in synucleinopathy models, Proc. Natl. Acad. Sci. USA sourceCould not verify

  The Discussion describes GBA mutations as increasing the risk of Parkinson’s disease and dementia with Lewy bodies, while the Results discuss tau aggregates in synucleinopathy mice. Searches for TSC1 and FTD found no passage addressing whether TSC1 mutations increase the risk of frontotemporal dementia with tau accumulation. The paper’s findings about GBA do not establish or contradict that claim. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

Glucosylsphingosine accumulates in GRN KO mice.

“Conversely, glucosylsphingosine, the substrate of GBA, accumulates in GRN KO mice, and GBA activity is reduced in these animals as well.130”

• cites [130] Platt, 2012, Lysosomal storage disorders: The cellular impact of lysosomal dysfunction, J. Cell Biol. sourceCould not verify

  The Clinical phenotypes of LSDs table lists glucosylsphingosine as a stored substrate in Gaucher disease, but it does not address GRN-knockout mice. Searches for GRN, progranulin, glucosylsphingosine, and reduced GBA activity found no passage reporting the claimed findings in those animals. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

Loss of function of GRN alkalinizes lysosomes.

“Similarly, loss of function of GRN alkalinizes lysosomes, while PD-associated mutations in TMEM175, a lysosomal proton leak channels, hyper-acidifies lysosomes.129,130”

• cites [129] Perry, 2017, Clinicopathological correlations in behavioural variant frontotemporal dementia, Brain sourceCould not verify

  The Genetic testing and Patient ascertainment and pathological diagnoses passages mention GRN mutations, but neither addresses lysosomes or their pH. Searches for GRN-related lysosomal alkalinization and for progranulin, lysosomal pH, and acidity found no passage supporting the claim. Page numbers were not available in our copy. (LLM, conf=0.72)

  Experimental — accuracy not yet measured
• cites [130] Platt, 2012, Lysosomal storage disorders: The cellular impact of lysosomal dysfunction, J. Cell Biol. sourceCould not verify

  The section on mitochondrial dysfunction and cytoplasmic protein aggregation discusses raised lysosomal pH in connection with presenilin-1, not GRN. Searches of our copy for GRN, progranulin, and lysosomal pH or acidification found no passage addressing whether GRN loss of function alkalinizes lysosomes. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

Inhibiting mTORC1 does not fully rescue tau degradation in TSC1 haploinsufficient iNeurons.

“Of note, inhibiting mTORC1 does not fully rescue tau degradation in TSC1 haploinsufficient iNeurons, suggesting that there are also mTORC1-independent mechanisms of tau accumulation in TSC1-mediated tauopathy.90”

• cites [90] Korvatska, 2013, Altered splicing of ATP6AP2causes X-linked parkinsonism with spasticity (XPDS), Hum. Mol. Genet sourceCould not verify

  The Discussion describes tau deposits and impaired lysosome-mediated protein degradation in XPDS brain, while the Results examine ATP6AP2 depletion and autophagy. Searches for TSC1-haploinsufficient iNeurons, mTORC1 inhibition, and rescue of tau degradation found no passage addressing that experiment. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

GBA activity is reduced in GRN KO mice.

“Conversely, glucosylsphingosine, the substrate of GBA, accumulates in GRN KO mice, and GBA activity is reduced in these animals as well.130”

• cites [130] Platt, 2012, Lysosomal storage disorders: The cellular impact of lysosomal dysfunction, J. Cell Biol. sourceCould not verify

  The Cellular metabolic stress section discusses glucocerebrosidase deficiency in Gaucher disease, but does not report GBA activity in GRN knockout mice. Searches for GRN, progranulin, and glucosylsphingosine found no passage in our copy addressing the claimed mouse finding. The indexed passages provide no page numbers. (LLM, conf=0.73)

  Experimental — accuracy not yet measured

Individuals with TSC1 mutations accumulate tau inclusions with abnormal acetylation distinct from the tau inclusions observed in AD and FTLD.

“Surprisingly, these individuals accumulate tau inclusions with abnormal acetylation distinct from the tau inclusions observed in AD and FTLD.90,140”

• cites [90] Korvatska, 2013, Altered splicing of ATP6AP2causes X-linked parkinsonism with spasticity (XPDS), Hum. Mol. Genet sourceCould not verify

  The Discussion reports pathological tau deposits in the striatum of an XPDS brain with ATP6AP2 deficiency, not in individuals with TSC1 mutations. Searches for TSC1, acetylated tau, and comparisons with AD or FTLD found no passage addressing the attributed claim. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [140] Sardi, 2017, Glucosylceramide synthase inhibition alleviates aberrations in synucleinopathy models, Proc. Natl. Acad. Sci. USA sourceCould not verify

  The Results describe tau aggregates in A53T-SNCA synucleinopathy mice, not in individuals with TSC1 mutations. Searches for TSC1, abnormal tau acetylation, and a comparison with AD or FTLD found no passage addressing those parts of the claim in our copy. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

Neurons rely heavily on local proteostasis that requires robust lysosomal trafficking and positioning due to their long axons and dendrites.

“At a mechanistic level, the long processes of axons and dendrites mean that neurons rely heavily on local proteostasis that requires robust lysosomal trafficking and positioning.154,155”

• cites [154] Walker, 2021, Dendritic Spines: Mediators of Cognitive Resilience in Aging and Alzheimer’s Disease, Neuroscientist sourceCould not verify

  The 'Regulation of Spine Morphology' section discusses microtubules delivering cargo to dendritic spines, but does not connect this to local proteostasis or lysosomal trafficking and positioning. Searches for those terms and for protein degradation along long axons and dendrites found no passage addressing the claimed mechanism; page numbers were unavailable in our copy. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [155] Wang, 2016, Essential control of mitochondrial morphology and function by chaperone-mediated autophagy through degradation of PARK7, Autophagy sourcePartly supported

  The Introduction links disrupted protein homeostasis to neurodegeneration, and the Results section ‘Degradation of PARK7 by lysosomes’ examines lysosomal protein degradation in a dopamine-neuron progenitor cell line. Neither passage addresses local proteostasis in axons or dendrites, or a need for lysosomal trafficking and positioning because of their length; those mechanistic parts of the claim are unsupported. (LLM, conf=0.77)

  Experimental — accuracy not yet measured

iNeurons are more resistant to the proteostatic stress induced by heavy metal toxicity.

“In our studies, we have found that iNeurons are more resistant to the proteostatic stress induced by heavy metal toxicity.164”

• cites [164] Yang, 2022, Lipid metabolism and storage in neuroglia: role in brain development and neurodegenerative diseases, Cell Biosci. 2022 12 sourceCould not verify

  The sections on neuroinflammation and oxidative stress and on glia–neuron coupling discuss lipid droplets, reactive oxygen species, and fatty-acid toxicity, not iNeurons’ resistance to proteostatic stress. Searches for iNeurons, heavy-metal toxicity, and proteostatic stress found no passage addressing the claim. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

Almost 50% of proteins in the mammalian proteome feature a KFERQ-like motif, including TDP-43, alpha-synuclein, APP, and tau.

“Almost 50% of the proteins in the mammalian proteome feature a KFERQ-like motif, including all the major aggregating proteins of neurodegenerative diseases (i.e., TDP-43, alpha-synuclein, APP, and tau).99,143–145”

• cites [99] Li, 2023, Disease-associated patterns of acetylation stabilize tau fibril formation, Structure sourceCould not verify

  The Introduction (page unavailable) discusses tau’s amyloid-forming motifs and mentions chaperone-mediated autophagy, but does not identify a KFERQ-like motif. Searches for KFERQ, the proteome percentage, and the named proteins found no passage addressing the claim. (LLM, conf=0.74)

  Experimental — accuracy not yet measured
• cites [143] Senkevich, 2023, GALC variants affect galactosylceramidase enzymatic activity and risk of Parkinson’s disease, Brain sourceCould not verify

  The Results section discusses GALC structure, and the Materials and methods section describes an alpha-synuclein assay. Neither the supplied passages nor searches for KFERQ-like motifs, the 50% estimate, TDP-43, APP, and tau found a passage addressing the claim. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [144] Simons, 2002, Overexpression of the myelin proteolipid protein leads to accumulation of cholesterol and proteolipid protein in endosomes/lysosomes: implications for Pelizaeus-Merzbacher disease, J. Cell Biol. sourceCould not verify

  The Discussion describes accumulation of proteolipid protein and cholesterol in endosomes/lysosomes, not KFERQ-like motifs. Searches for the motif, the 50% proteome estimate, and the named neurodegeneration-related proteins found no passage addressing the claim in our copy. (LLM, conf=0.78)

  Experimental — accuracy not yet measured
• cites [145] Singh, 2021, Pharmacological rescue of impaired mitophagy in Parkinson’s disease-related LRRK2 G2019S knock-in mice, Elife sourceCould not verify

  The Introduction discusses LRRK2 in Parkinson’s disease, and the Results examine mitophagy and macroautophagy; neither addresses the prevalence of KFERQ-like motifs or whether TDP-43, alpha-synuclein, APP, and tau contain them. Searches of our full-text copy for “KFERQ,” the 50% proteome figure, and the named proteins found no passage establishing the claim. (LLM, conf=0.75)

  Experimental — accuracy not yet measured

Cathepsin D knockout mice accumulate Ab in addition to lipofuscin.

“As an example, cathepsin D knockout mice accumulate Ab in addition to lipofuscin, and Alzheimer’s pathology has been observed in postmortem tissues from several NCL patients.125–127”

• cites [125] Pará, 2020, Neuropathophysiology of lysosomal storage diseases: synaptic dysfunction as a starting point for disease progression, J. Clin. Med sourceCould not verify

  Section 3 links cathepsin D deficiency to NCL10 but discusses synaptic vesicle recycling, not deposits in knockout mice. The Introduction mentions amyloid-β in multiple lysosomal storage diseases, and Section 4 describes storage material in CLN5 patient-derived cells; neither establishes that cathepsin D knockout mice accumulate amyloid-β and lipofuscin. Searched for cathepsin D knockout, amyloid-β, and lipofuscin. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [126] Parenti, 2021, The rapidly evolving view of lysosomal storage diseases, EMBO Mol. Med sourcePartly supported

  The Secondary storage section (page unavailable) reports amyloid-β accumulation in lysosomal storage diseases generally. It does not say that cathepsin D knockout mice accumulate amyloid-β or lipofuscin; searches for cathepsin D and lipofuscin found no passage establishing that specific finding. (LLM, conf=0.79)

  Experimental — accuracy not yet measured
• cites [127] Park, 2015, The role of ATP13A2 in Parkinson’s disease: clinical phenotypes and molecular mechanisms, Mov. Disord. sourceNot checked — no full text of the source

TSC is recognized as a juvenile tauopathy.

“Tubers isolated from infants with TSC1 mutations demonstrate hyperphosphorylated tau and thus it is recognized as a “juvenile tauopathy.”139”

• cites [139] Sampognaro, 2023, Mutations in α-synuclein, TDP-43 and tau prolong protein half-life through diminished degradation by lysosomal proteases, Mol. Neurodegener. sourcePartly supported

  The References section lists a study titled “TSC1 loss increases risk for tauopathy,” which supports a connection between TSC1 loss and tauopathy. Our copy does not say that TSC is recognized as a juvenile tauopathy or report hyperphosphorylated tau in tubers from infants; the Results and Discussion passages concern tau degradation instead. No page numbers are available in our copy. (LLM, conf=0.78)

  Experimental — accuracy not yet measured

PD-associated mutations in TMEM175 hyper-acidify lysosomes.

“Similarly, loss of function of GRN alkalinizes lysosomes, while PD-associated mutations in TMEM175, a lysosomal proton leak channels, hyper-acidifies lysosomes.129,130”

• cites [129] Perry, 2017, Clinicopathological correlations in behavioural variant frontotemporal dementia, Brain sourceCould not verify

  The Genetic testing and Patient ascertainment and pathological diagnoses sections discuss GRN and other mutations, but do not mention TMEM175 or lysosomal acidity. Searches for TMEM175 hyper-acidification and lysosomal proton leak found no passage addressing the claim. (LLM, conf=0.78)

  Experimental — accuracy not yet measured
• cites [130] Platt, 2012, Lysosomal storage disorders: The cellular impact of lysosomal dysfunction, J. Cell Biol. sourceCould not verify

  The paper’s section on endosomal–autophagic–lysosomal function describes lysosomal acidity, but does not address TMEM175 mutations or hyper-acidification. Searches for TMEM175, Parkinson-associated mutations, and proton leak channels found no passage supporting the attributed claim. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

There are mTORC1-independent mechanisms of tau accumulation in TSC1-mediated tauopathy.

“Of note, inhibiting mTORC1 does not fully rescue tau degradation in TSC1 haploinsufficient iNeurons, suggesting that there are also mTORC1-independent mechanisms of tau accumulation in TSC1-mediated tauopathy.90”

• cites [90] Korvatska, 2013, Altered splicing of ATP6AP2causes X-linked parkinsonism with spasticity (XPDS), Hum. Mol. Genet sourceCould not verify

  The Discussion describes ATP6AP2 deficiency, tau deposits, and impaired protein degradation in XPDS brain; the Results report impaired autophagy in the XPDS striatum. Searches for TSC1 haploinsufficient iNeurons, mTORC1 inhibition, and mTORC1-independent tau accumulation found no passage addressing those claims in this paper. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

Loss of function of PS1 alkalinizes lysosomes.

“For example, loss of function of PS1, mutations of which cause early-onset AD, alkalinize lysosomes.128”

• cites [128] Park, 2020, Potential therapeutic target for aging and age-related neurodegenerative diseases: the role of acid sphingomyelinase, Exp. Mol. Med. 2020 52 sourceCould not verify

  The “ASM in Alzheimer’s disease” section mentions APP/PS1 mice and changes in lysosomal markers, but does not say that loss of PS1 function alkalinizes lysosomes. Searches for PS1 loss of function, lysosomal acidity, and alkalinization found no passage addressing that claim; page numbers were unavailable. (LLM, conf=0.75)

  Experimental — accuracy not yet measured

Many LSDs feature neurological symptoms.

“As a result, it is unsurprising that many LSDs feature neurological symptoms.”

At periods of highest proteostatic stress, cells are most vulnerable to lysosomal dysfunction.

“Thus, it follows that at periods of highest proteostatic stress, cells would be rendered most vulnerable to lysosomal dysfunction.”

Optimal cell division and development rely on functional lysosomes.

“Starting from the earliest embryonic stage, optimal cell division and development rely on functional lysosomes.”

• cites [15] Bankston, 2019, Autophagy is essential for oligodendrocyte differentiation, survival, and proper myelination, Glia sourceNot checked — no full text of the source

Development and aging represent two life epochs with high metabolic stress.

“The massive cell division and apoptosis of development and the accumulation of environmental and other stressors of aging represent two life epochs with such high metabolic stress.”

Individual genetic variations and differences in environmental exposures can cause these life epochs to overlap in regard to age of disease presentation.

“While depicted as separate in Figure 1, in reality, individual genetic variations and differences in environmental exposures can cause these life “epochs” to overlap in regard to age of disease presentation.”

Lysosomal fusion is implicated in the development of the growth cone and presynapse.

“On the axonal side of the synapse, lysosomal fusion is implicated in the development of the growth cone and presynapse.33”

• cites [33] Clark, 1995, The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families, Nat. Genet. 1995 11 sourceNot checked — no full text of the source

Myelin is compacted by autophagic removal of the cytosol to form a tight sheath.

“There, the myelin is compacted by autophagic removal of the cytosol to form a tight sheath.38”

• cites [38] Cruts, 2006, Progranulin mutations in ubiquitin-positive frontotemporal dementia linked to chromosome 17q21, Curr. Alzheimer Res sourceNot checked — no full text of the source

The lysosome is necessary for numerous components of both prenatal and postnatal development within a variety of CNS cell types.

“Overall, the lysosome is necessary for numerous components of both prenatal and postnatal development within a variety of CNS cell types.”

Later in life, heterozygous mutation carriers become susceptible to disease as lysosomes cannot resolve the accumulated stressors of aging.

“Then, later in life, heterozygous mutation carriers become susceptible to disease as lysosomes cannot resolve the accumulated stressors of aging (Figure 2).”

• AssumptionThe authors state this as an assumption: Aging acts as a second hit that unmasks heterozygous lysosomal mutations and leads to adult neurodegenerative disease.

The predominance of neurological phenotypes in individuals with LSDs underscores the metabolic demands of the CNS.

“Intact lysosomal function is vital for the brain to successfully emerge from development, and the predominance of neurological phenotypes in individuals with LSDs underscores the metabolic demands of the CNS.14”

• cites [14] Ballabio, 2009, Lysosomal disorders: From storage to cellular damage, Biochimica et Biophysica Acta (BBA) Molecular Cell Research sourceNot checked — no full text of the source

Oligodendrocytes accumulate and store a myelin precursor, proteolipid protein (PLP), in the late endosome/lysosome.

“Further, oligodendrocytes accumulate and store a myelin precursor, proteolipid protein (PLP), in the late endosome/lysosome.36”

• cites [36] Craiu, 2015, Rett-like onset in late-infantile neuronal ceroid lipofuscinosis (CLN7) caused by compound heterozygous mutation in the MFSD8 gene and review of the literature data on clinical onset signs, Eur. J. Paediatr. Neurol. sourceNot checked — no full text of the source

Cumulative environmental stressors can, over time, impair the very processes that are used to repair their damage.

“Cumulative environmental stressors can, over time, impair the very processes that are used to repair their damage.”

The clinical and pathologic overlap between neurodevelopmental and neurodegenerative disorders involving the lysosome provides insight into their pathophysiology.

“The clinical and pathologic overlap between neurodevelopmental and neurodegenerative disorders involving the lysosome also provides insight into their pathophysiology and will be discussed below.”

Aging appears to represent the confluence of both diminished lysosomal function and accumulating need for lysosomal catabolism.

“Overall, aging appears to represent the confluence of both diminished lysosomal function and accumulating need for lysosomal catabolism.”

Both lipid and carbohydrate metabolism are disrupted in LSDs and neurodegeneration throughout the lifespan.

“Importantly, while abnormal proteostasis is a hallmark of aging and misfolded proteins are a key feature in both LSDs and neurodegeneration, other macromolecules are processed by the lysosome, evidenced by the finding that both lipid and carbohydrate metabolism are disrupted in these diseases throughout the lifespan.12,13”

• cites [12] Baker, 2006, Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17, Nature 2006 442 sourceNot checked — no full text of the source
• cites [13] Ballabio, 2019, Lysosomes as dynamic regulators of cell and organismal homeostasis, Nat. Rev. Mol. Cell Biol. 2019 21 sourceNot checked — no full text of the source

Synaptic dysfunction is a key finding in many lysosomal storage disorders.

“As evidence of its importance in these processes, synaptic dysfunction is a key finding in many lysosomal storage disorders.34”

• cites [34] Cornejo, 2017, Global and local mechanisms sustain axonal proteostasis of transmembrane proteins, Traffic sourceNot checked — no full text of the source

Aging acts as the second mutant allele in neurodevelopmental disorders.

“In essence, aging acts as the second mutant allele in neurodevelopmental disorders.”

• AssumptionThe authors state this as an assumption: Aging acts as a second hit that unmasks heterozygous lysosomal mutations and leads to adult neurodegenerative disease.

Genetic disorders of lysosomal clearance manifest during development and aging.

“This may also explain why genetic disorders of lysosomal clearance manifest during these two periods.”

Development is the first life epoch of significant proteostatic and metabolic stress.

“Development is the first life epoch of significant proteostatic and metabolic stress (Figure 1, Epoch 1).”

In transdifferentiated neurons from aging and Alzheimer's disease patients, there is lysosomal alkanization.

“Similarly, in transdifferentiated neurons from aging and Alzheimer’s disease patients, there is lysosomal alkanization.59”

• cites [59] Gallotta, 2020, Extracellular proteostasis prevents aggregation during pathogenic attack, Nature 2020 584 sourceNot checked — no full text of the source

Upon signaling from neurons, PLP is exocytosed to the plasma membrane to form the myelin sheath.

“Upon signaling from neurons, PLP is exocytosed to the plasma membrane to form the myelin sheath.37”

• cites [37] Cruts, 2006, Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21, Nature 2006 442 sourceNot checked — no full text of the source

Lysosomes are important for synaptic structure and function.

“Lysosomes are also important for synaptic structure and function.”

• cites [28] Canafoglia, 2014, Recurrent generalized seizures, visual loss, and palinopsia as phenotypic features of neuronal ceroid lipofuscinosis due to progranulin gene mutation, Epilepsia sourceNot checked — no full text of the source

Lysosomal function is critical for cellular metabolism and homeostasis.

“Thus, lysosomal function is critical for cellular metabolism and homeostasis.”

The second epoch of enhanced proteostatic and metabolic stress occurs with aging.

“The second epoch of enhanced proteostatic and metabolic stress occurs with aging (Figure 1, Epoch 2).”

The nervous system is the earliest and most profoundly affected in these diseases connected by the lysosome.

“Most obviously, the nervous system is the earliest and most profoundly affected in these diseases connected by the lysosome.6”

• cites [6] Almeida, 2016, Portuguese family with the co-occurrence of frontotemporal lobar degeneration and neuronal ceroid lipofuscinosis phenotypes due to progranulin gene mutation, Neurobiol. Aging sourceNot checked — no full text of the source

Intact lysosomal function is vital for the brain to successfully emerge from development.

“Intact lysosomal function is vital for the brain to successfully emerge from development, and the predominance of neurological phenotypes in individuals with LSDs underscores the metabolic demands of the CNS.14”

• cites [14] Ballabio, 2009, Lysosomal disorders: From storage to cellular damage, Biochimica et Biophysica Acta (BBA) Molecular Cell Research sourceNot checked — no full text of the source

The early and later-life stress epochs requiring relatively increased lysosomal capacity may explain why lysosomes lie at the nexus of genetic neurodevelopmental and neurodegenerative disorders.

“The early and later-life stress epochs requiring relatively increased lysosomal capacity may explain why lysosomes lie at the nexus of genetic neurodevelopmental and neurodegenerative disorders.”

Chaperone-mediated autophagy diminishes with age.

“Additionally, chaperone-mediated autophagy (CMA), described in detail below, diminishes with age.61”

• cites [61] Geisler, 2010, PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1, Nat. Cell Biol. sourceNot checked — no full text of the source

In primary mouse neuron culture, more days in vitro results in de-acidification of lysosomes, particularly in neurites.

“In primary mouse neuron culture, more days in vitro (DIV) results in de-acidification of lysosomes, particularly in neurites.58”

• cites [58] Gallala, 2011, Biological function of the cellular lipid bmp-bmp as a key activator for cholesterol sorting and membrane digestion, Neurochem. Res sourceNot checked — no full text of the source

The lysosome and its proteases are vital for preventing diseases of protein misfolding.

“Though many cellular components contribute to maintaining proteostasis, the lysosome and its many proteases are vital for preventing diseases of protein misfolding.”

The machinery of the lysosome itself appears to diminish with age.

“Finally, the machinery of the lysosome itself appears to diminish with age.”

In addition to the LSDs, other lysosomal neurogenetic disorders have been linked to adult neurodegenerative disease.

“In addition to the LSDs, other lysosomal neurogenetic disorders have been linked to adult neurodegenerative disease.”

Sphingolipid imbalance has been observed in lipidomic studies of neurodegenerative diseases, including PD.

“Sphingolipid imbalance has been observed in lipidomic studies of neurodegenerative diseases, including PD.95”

• cites [95] Lawrence, 2019, The lysosome as a cellular centre for signalling, metabolism and quality control, Nat. Cell Biol. 2019 21 sourceNot checked — no full text of the source

Neurodegeneration is seen phenotypically as developmental milestones are initially gained normally and then lost with disease progression.

“In these cases, neurodegeneration is seen phenotypically as developmental milestones are initially gained normally and then lost with disease progression.”

Three genes have even more controversial links to PD: ARSA, NPC1 and NPC2.

“Three genes have even more controversial links to PD: ARSA, NPC1 and NPC2.”

The majority of these genes had been previously defined, based on electron microscopy findings, as lysosomal storage diseases.

“Among these, the majority had been previously defined, based on electron microscopy findings, as lysosomal storage diseases.”

Reduced clearance of sphingolipids due to loss of sphingolipid progressing enzymes such as GBA may exacerbate derangements of sphingolipid levels with aging, impacting lysosomal function.

“Thus, reduced clearance of sphingolipids due to loss of sphingolipid progressing enzymes such as GBA may exacerbate derangements of sphingolipid levels with aging, impacting lysosomal function.”

Neuronal loss is a shared feature of both LSDs and adult neurodegenerative disorders.

“Thus, neuronal loss is a shared feature of both LSDs and adult neurodegenerative disorders.”

While these are generally disorders of infancy and childhood, the neurological phenotypes of LSDs typically represent both a failure of appropriate development as well as neurodegeneration.

“Importantly, while these are generally disorders of infancy and childhood, the neurological phenotypes of LSDs typically represent both a failure of appropriate development as well as neurodegeneration.14”

• cites [14] Ballabio, 2009, Lysosomal disorders: From storage to cellular damage, Biochimica et Biophysica Acta (BBA) Molecular Cell Research sourceNot checked — no full text of the source

Altered sphingolipid metabolism may promote alpha-synuclein accumulation.

“Specific to PD pathology, altered sphingolipid metabolism may promote alpha-synuclein accumulation.”

Mono-allelic GRN mutation carriers have lipofuscinosis accumulation similar to the NCLs.

“It was additionally observed that mono-allelic GRN mutation carriers have lipofuscinosis accumulation similar to the NCLs, suggesting overlapping disease processes.117”

• cites [117] Nichols, 2005, Genetic screening for a single common LRRK2 mutation in familial Parkinson’s disease, Lancet sourceNot checked — no full text of the source

When the genes are organized based on disease family, a correlation, albeit non-perfect, between pediatric disease family and a particular adult neurodegenerative disease becomes apparent.

“When the genes are organized based on disease family (Table 1), a correlation, albeit non-perfect, between pediatric disease family and a particular adult neurodegenerative disease becomes apparent.”

Mutations or disease states that alter lysosomal pH impact the ability of the lysosome to catabolize proteins.

“Most cathepsins operate optimally at the acidic pH of the lysosome. Thus, mutations or disease states that alter lysosomal pH impact the ability of the lysosome to catabolize proteins.127”

• cites [127] Park, 2015, The role of ATP13A2 in Parkinson’s disease: clinical phenotypes and molecular mechanisms, Mov. Disord. sourceNot checked — no full text of the source

Differences in specificity of NCL-associated proteins may explain why there is a wider variety of neurodegenerative diseases linked to NCL genes.

“These differences in specificity of NCL-associated proteins may explain why there is a wider variety of neurodegenerative diseases linked to NCL genes (Table 1).”

Reduced activity of a specific cathepsin may result in the preferential accumulation of some proteins over others.

“Thus, reduced activity of a specific cathepsin may result in the preferential accumulation of some proteins over others.”

In vitro, progranulin promotes the autoactivation of procathepsin D into the mature form, enhancing its activity.

“In vitro, progranulin promotes the autoactivation of the proprotein of cathepsin D into the mature form, thus enhancing its activity.132”

• cites [132] Polymeropoulos, 1997, Mutation in the α-synuclein gene identified in families with Parkinson’s disease, Science sourceNot checked — no full text of the source

Progranulin is a cathepsin-modifying protein.

“Progranulin, in fact, is one of these cathepsin-modifying proteins.”

Tau acetylation promotes tau fibrillation.

“Tau acetylation contributes to tau pathology via multiple potential mechanisms: promoting tau fibrillation146 and impairing tau clearance through CMA both by reducing entry into the lysosome and proteolysis by the lysosome.147”

• cites [146] Smith, 2012, Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage, Am. J. Hum. Genet sourceNot checked — no full text of the source

In CMA, proteins containing a KFERQ-like degradation signal are recognized by Hsc70 and directly transported into the lysosome through LAMP2A.

“In CMA, proteins containing a KFERQ-like degradation signal are recognized by heat shock cognate 71 kDA protein (Hsc70) and directly transported into the lysosome through the transmembrane channel LAMP2A.142”

• cites [142] Schröder, 2010, The proteome of lysosomes, Proteomics sourceNot checked — no full text of the source

Shared disease genes impair lysosomal catabolic function.

“Because the shared disease genes impair lysosomal catabolic function, we propose that they collectively be referred to as lysosomal clearance disorders.”

The mechanistic basis for TSC1-mediated tauopathy involves the role of the TSC1/hamartin protein in autophagy.

“The mechanistic basis for this involves the role of the TSC1/hamartin protein in autophagy.”

CMA is diminished with age.

“First, CMA is diminished with age, thus genetic risk alleles may combine with aging to lead to late-onset neurodegeneration.61”

• cites [61] Geisler, 2010, PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1, Nat. Cell Biol. sourceNot checked — no full text of the source

The intersection between GRN and GBA1-mediated pathologies could contribute to the co-pathology observed in these diseases.

“Thus, the clear intersection between GRN and GBA1-mediated pathologies could contribute to the co-pathology observed in these diseases.”

Loss of vATPase would be expected to impair processing of numerous substrates.

“Lysosomal acidification is maintained by the vATPase, a proton pump responsible for acidifying the lysosome, and loss of vATPase would be expected to impair processing of numerous substrates.”

Genetic risk alleles may combine with aging to lead to late-onset neurodegeneration.

“First, CMA is diminished with age, thus genetic risk alleles may combine with aging to lead to late-onset neurodegeneration.61”

• cites [61] Geisler, 2010, PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1, Nat. Cell Biol. sourceNot checked — no full text of the source

Most cathepsins operate optimally at the acidic pH of the lysosome.

“Most cathepsins operate optimally at the acidic pH of the lysosome. Thus, mutations or disease states that alter lysosomal pH impact the ability of the lysosome to catabolize proteins.127”

• cites [127] Park, 2015, The role of ATP13A2 in Parkinson’s disease: clinical phenotypes and molecular mechanisms, Mov. Disord. sourceNot checked — no full text of the source

Neurons are particularly susceptible to lysosomal dysfunction.

“For reasons that are not yet entirely clear, neurons are particularly susceptible to lysosomal dysfunction.”

Failure to clear acetylated tau leads to a novel TSC tauopathy.

“The resultant failure to clear acetylated tau leads to a novel TSC tauopathy.148”

• cites [148] Stevens, 2007, The classical complement cascade mediates CNS synapse elimination, Cell sourceNot checked — no full text of the source

Most lysosomal storage disorders feature neurological symptoms such as vision impairment and seizures early in disease progression.

“Clinically, this is evidenced by the fact that most lysosomal storage disorders feature neurological symptoms such as vision impairment and seizures early in disease progression.”