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Cited by 37Lysosomal Storage Disorders ResearchSphingolipid Metabolism and SignalingNeuroinflammation and Neurodegeneration Mechanisms

Genetic defects in the sphingolipid degradation pathway and their effects on microglia in neurodegenerative disease

Open access
Allende, Maria L., Zhu, Hongling, Kono, Mari, Hoachlander-Hobby, Lila E., Huso, Vienna L., Proia, Richard L.·2021·Cellular Signalling
DOI 10.1016/j.cellsig.2020.109879PMC PMC7775721
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Abstract

Sphingolipids, which function as plasma membrane lipids and signaling molecules, are highly enriched in neuronal and myelin membranes in the nervous system. They are degraded in lysosomes by a defined sequence of enzymatic steps. In the related group of disorders, the sphingolipidoses, mutations in the genes that encode the individual degradative enzymes cause lysosomal accumulation of sphingolipids and often result in severe neurodegenerative disease. Here we review the information indicating that microglia, which actively clear sphingolipid-rich membranes in the brain during development and homeostasis, are directly affected by these mutations and promote neurodegeneration in the sphingolipidoses. We also identify parallels between the sphingolipidoses and more common forms of neurodegeneration, which both exhibit evidence of defective sphingolipid clearance in the nervous system.

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Crossref · 10.1016/j.cellsig.2020.109879

Cites

128 of 130 references verified2 citation errors · 0 not checkable

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  • Lysosomes require a highly acidic pH (~4.5-4.7) achieved through import of protons from the cytosol into the organellar lumen.

    “To function effectively, lysosomes require a highly acidic pH (~4.5 – 4.7) that is achieved through import of protons from the cytosol into the organellar lumen.4”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [4]

    The Introduction describes sphingolipid degradation in lysosomes and names acid-dependent enzymes, but does not give a lysosomal pH or explain how lysosomes are acidified. Searches of our copy for pH 4.5–4.7, proton import, and lysosomal acidification found no passage addressing those parts of the claim. (LLM, conf=0.75)

    Experimental — accuracy not yet measured

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Research works printed but not linked: 3

  1. [25]Beutler E, Grabowski GA, Gaucher Disease, Scriver CR, Beaudet AL, Sly WS, Valle D (Eds). McGraw-Hill, NY, USA, In: The Metabolic and Molecular Bases of Inherited Disease, 2001, pp. 3635– 3668
  2. [57]Suzuki Y, Oshima A, Nanba E, Beta-galactosidase deficiency (beta-galactosidosis): GM1 gangliosidosis and Morquio B disease, Scriver CR, Beaudet AL, Sly WS, Valle D (Eds). McGraw-Hill, NY, USA, In: The Metabolic and Molecular Bases of Inherited Disease., 2001, pp. 3775– 3809.
  3. [98]Gravel RA, Kaback MM, Proia RL, Sandhoff K, Suzuki K, Suzuki K, The GM2 gangliosidoses, Scriver CR, Beaudet AL, Valle D, Sly WS, Childs B, Kinzler KW and Vogelstein B (eds). McGraw-Hill, NY, USA, In: The Metabolic and Molecular Basis of Inherited Disease., 2001, pp. 3827– 3876.

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Authors
Allende, M. L., Zhu, H., Kono, M., Hoachlander-Hobby, L. E., Huso, V. L., & Proia, R. L.
Affiliations
National Institutes of Health (US)
Corresponding author
Proia, Richard L.
ORCID
Venue
Cellular Signalling
Publisher
Elsevier BV
Published
2021-02
Volume
78
Pages
109879
ISSN
0898-6568 (ISSN-L)
DOI
10.1016/j.cellsig.2020.109879
PMC
PMC7775721
OpenAlex
W3111719647
Cited by
37
References
130
Citations by year
2026: 4 · 2025: 9 · 2024: 8 · 2023: 6 · 2022: 5 · 2021: 5
FWCI
2.41
Type
journal article
Language
en
Open access
Licence
Locations
  • Cellular Signalling (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of Diabetes and Digestive and Kidney Diseases
Topics
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
sphingolipid degradation, sphingolipidosis, microglia, lysosomal storage disease, neurodegeneration, lysosomal accumulation, myelin, neurodegenerative diseases
MeSH terms
Animals, Humans, Mutation, Sphingolipidoses, Sphingolipids, Signal Transduction, Microglia, Neurodegenerative Diseases

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