Glucosylceramide synthase inhibition alleviates aberrations in synucleinopathy models
Open accessAbstract
Significance Mutations in the glucocerebrosidase gene ( GBA ) represent the most common genetic risk factor for Parkinson’s disease (PD), affecting 5–10% of patients and accelerating disease progression. Mutations in GBA and consequent loss of enzymatic activity allow glucocerebrosides to build up in cells. Here, we tested an experimental drug that inhibits the production of glucocerebrosides, hypothesizing that producing fewer lipids may counteract the challenge of clearing them from cells. In mice with mutant Gba , prolonged administration of this inhibitor reduced brain glucocerebrosides. In addition, this treatment reduced levels of aggregated α-synuclein, a protein that builds up in PD brains, and improved behavioral responses. The findings suggest that reducing glucocerebrosides might represent a viable therapeutic strategy for PD patients carrying GBA mutations.
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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”
From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [140]
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 measuredTSC1 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”
From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [140]
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)
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Tong, B., Ba, Y., Li, Z., Yang, C., Su, K., Qi, H., Zhang, D., Liu, X., Wu, Y., Chen, Y., et al. (2024) · Neurobiology of Disease · doi:10.1016/j.nbd.2024.106505 · Cited by 117 · see citing works
Preserving Lysosomal Function in the Aging Brain: Insights from Neurodegeneration
Peng, W., Minakaki, G., Nguyen, M., & Krainc, D. (2019) · Neurotherapeutics · doi:10.1007/s13311-019-00742-3 · Cited by 79 · see citing works
Dysregulation of the autophagic-lysosomal pathway in Gaucher and Parkinson's disease
Pitcairn, C., Wani, W. Y., & Mazzulli, J. R. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2018.03.008 · Cited by 75 · see citing works
Lane-Donovan, C., Paredes, M., & Kao, A. W. (2025) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2025.102854 · Cited by 3 · see citing works
- Authors
- Sardi, S. P., Viel, C., Clarke, J., Treleaven, C. M., Richards, A. M., Park, H., Olszewski, M. A., Dodge, J. C., Marshall, J., Makino, E., Wang, B., Sidman, R. L., Cheng, S. H., & Shihabuddin, L. S.
- Affiliations
- Neuroscience, Sanofi, Framingham, MA 01701;
- Rare Diseases, Sanofi, Framingham, MA 01701;
- Analytical R&D, Sanofi, Waltham, MA 02451;
- Beth Israel Deaconess Medical Center (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2017-02-21
- Volume
- 114
- Issue
- 10
- Pages
- 2699-2704
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5347608
- OpenAlex
- W2589161214
- Cited by
- 203
- References
- 2
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 24 · 2023: 13 · 2022: 25 · 2021: 41 · 2020: 30 · 2019: 28 · 2018: 19 · 2017: 6 · 2013: 1
- FWCI
- 16.80
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Internal funding for Neuro Rare Diseases program at Sanofi Genzyme (none)
- Topics
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
- Keywords
- glucosylceramide synthase inhibition, glucocerebrosidase mutations, Parkinson's disease, glucosylceramide, alpha-synuclein aggregation, synucleinopathies, lipid metabolism, treatment options
- MeSH terms
- Animals, Carbamates, Disease Models, Animal, Enzyme Inhibitors, Gene Expression Regulation, Glucosyltransferases, Humans, Mutation, Parkinson Disease, Quinuclidines, tau Proteins, Ubiquitin, Mice, alpha-Synuclein, Protein Aggregation, Pathological
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