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Lysosomal fusion and SNARE function are impaired by cholesterol accumulation in lysosomal storage disorders
Open accessAbstract
The function of lysosomes relies on the ability of the lysosomal membrane to fuse with several target membranes in the cell. It is known that in lysosomal storage disorders (LSDs), lysosomal accumulation of several types of substrates is associated with lysosomal dysfunction and impairment of endocytic membrane traffic. By analysing cells from two severe neurodegenerative LSDs, we observed that cholesterol abnormally accumulates in the endolysosomal membrane of LSD cells, thereby reducing the ability of lysosomes to efficiently fuse with endocytic and autophagic vesicles. Furthermore, we discovered that soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptors (SNAREs), which are key components of the cellular membrane fusion machinery are aberrantly sequestered in cholesterol-enriched regions of LSD endolysosomal membranes. This abnormal spatial organization locks SNAREs in complexes and impairs their sorting and recycling. Importantly, reducing membrane cholesterol levels in LSD cells restores normal SNARE function and efficient lysosomal fusion. Our results support a model by which cholesterol abnormalities determine lysosomal dysfunction and endocytic traffic jam in LSDs by impairing the membrane fusion machinery, thus suggesting new therapeutic targets for the treatment of these disorders.
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“Therefore, defective lipid droplet clearance and elevated lipid and crystal burden in lysosomes could adversely interact with myelin-debris degradation within lysosomes, although it remains plausible that peroxisomes affect degradation of endolysosomal cargo independent of lipid droplet clearing mechanisms, including via generation of radical nitrogen and oxygen species (3).”
From Peroxisomal integrity in demyelination-associated microglia enables cellular debris clearance and myelin renewal in mice (2026) · cites this paper as [51]
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“Excess cholesterol can also interfere with SNARE-mediated fusion of endosomes and lysosomes with autophagosomes and phagosomes (Fraldi et al., 2010).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Fraldi et al., 2010
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“In lysosomal storage disorders, increased cholesterol sequesters VAMP7/8 within endolysosomal membranes and prevents their recycling for continued rounds of organelle fusion (Fraldi et al., 2010).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Fraldi et al., 2010
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Metadata
- Authors
- Fraldi, A., Annunziata, F., Lombardi, A., Kaiser, H., Medina, D. L., Spampanato, C., Fedele, A. O., Polishchuk, R., Sorrentino, N. C., Simons, K., & Ballabio, A.
- Affiliations
- Telethon Institute Of Genetics And Medicine (IT)
- Max Planck Institute of Molecular Cell Biology and Genetics (DE)
- Mario Negri Sud Foundation (IT)
- Federico II University Hospital (IT)
- Corresponding author
- Ballabio, Andrea
- ORCID
- Venue
- The EMBO Journal
- Published
- 2010-09-24
- Volume
- 29
- Issue
- 21
- Pages
- 3607-3620
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC2982760
- OpenAlex
- W2157973824
- Cited by
- 225
- References
- 52
- Citations by year
- 2026: 10 · 2025: 5 · 2024: 5 · 2023: 14 · 2022: 15 · 2021: 20 · 2020: 16 · 2019: 17 · 2018: 14 · 2017: 15 · 2016: 18 · 2015: 17 · 2014: 16 · 2013: 20 · 2012: 13
- FWCI
- 9.30
- Type
- journal article
- Language
- en
- Update notices
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Fondazione Telethon
- Topics
- Health Sciences › Medicine › Genetics (clinical) › Lysosomal Storage Disorders Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Keywords
- lysosomal storage disease, cholesterol accumulation, SNARE proteins, autophagic vesicles, lysosomal dysfunction, neurodegenerative diseases, membrane cholesterol, therapeutic target
- MeSH terms
- Animals, Autophagy, Cells, Cultured, Cholesterol, Embryo, Mammalian, Endocytosis, Fibroblasts, Fluorescent Antibody Technique, Immunoenzyme Techniques, Lysosomes, Membrane Fusion, Phospholipids, RNA, Messenger, Blotting, Western, Lysosomal Storage Diseases, Reverse Transcriptase Polymerase Chain Reaction, Immunoprecipitation, SNARE Proteins, Mice, Lysosomal Membrane Proteins, Lysosomal-Associated Membrane Protein 1, ErbB Receptors
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