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Cited by 689Lysosomal Storage Disorders ResearchGlycogen Storage Diseases and MyoclonusBiomedical Research and Pathophysiology

Lysosomal storage disorders: The cellular impact of lysosomal dysfunction

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Platt, Frances M., Boland, Barry, van der Spoel, Aarnoud C.·2012·Journal of Cell Biology
DOI 10.1083/jcb.201208152PMC PMC3514785
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Abstract

Lysosomal storage diseases (LSDs) are a family of disorders that result from inherited gene mutations that perturb lysosomal homeostasis. LSDs mainly stem from deficiencies in lysosomal enzymes, but also in some non-enzymatic lysosomal proteins, which lead to abnormal storage of macromolecular substrates. Valuable insights into lysosome functions have emerged from research into these diseases. In addition to primary lysosomal dysfunction, cellular pathways associated with other membrane-bound organelles are perturbed in these disorders. Through selective examples, we illustrate why the term "cellular storage disorders" may be a more appropriate description of these diseases and discuss therapies that can alleviate storage and restore normal cellular function.

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  • 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”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [130]

    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

  • 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”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [130]

    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

  • BMP levels are reduced in the brains of GRN KO mice and the CSF of patients with GRN-FTD.

    “BMP levels are reduced in the brains of GRN KO mice and the CSF of patients with GRN-FTD.”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [130]

    The Clinical phenotypes of LSDs section discusses brain pathology in lysosomal storage disorders but does not report BMP measurements in GRN-knockout mice or patients with GRN-FTD. Searches for the claim and for BMP, progranulin, and GRN found no passage addressing those measurements in our copy. (LLM, conf=0.77)

    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”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [130]

    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

  • 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”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [130]

    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

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Cited by

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Authors
Platt, F. M., Boland, B., & van der Spoel, A. C.
Affiliations
  • University of Oxford (GB)
  • Conway Institute, School of Biomolecular and Biomedical Science, University of Dublin, Belfield, Dublin 4, Ireland 2
  • Atlantic Research Centre, Departments of Pediatrics and Biochemistry & Molecular Biology, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada 3
Corresponding author
  • Platt, Frances M.
  • Boland, Barry
ORCID
Venue
Journal of Cell Biology
Publisher
Rockefeller University Press
Published
2012-11-26
Volume
199
Issue
5
Pages
723-734
ISSN
  • 0021-9525 (ISSN-L)
  • 1540-8140
DOI
10.1083/jcb.201208152
PMC
PMC3514785
OpenAlex
W1900339045
Cited by
689
References
8
Citations by year
2026: 25 · 2025: 35 · 2024: 40 · 2023: 40 · 2022: 54 · 2021: 64 · 2020: 65 · 2019: 59 · 2018: 58 · 2017: 55 · 2016: 62 · 2015: 59 · 2014: 45 · 2013: 27
FWCI
4.57
Type
journal article
Language
en
Open access
Locations
  • The Journal of Cell Biology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • DalSpace (Dalhousie University) (submittedVersion)
Topics
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
  • Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Biomedical Research and Pathophysiology
Keywords
lysosomal storage disease, lysosomal dysfunction, lysosomal homeostasis, lysosomal enzyme deficiency, membrane-bound organelles, lysosomal function, lysosomal storage disease therapy
MeSH terms
Animals, Cell Biology, Humans, Lysosomes, Models, Biological, Phenotype, Lysosomal Storage Diseases

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