Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies
Open accessAbstract
Parkinson's disease (PD), an adult neurodegenerative disorder, has been clinically linked to the lysosomal storage disorder Gaucher disease (GD), but the mechanistic connection is not known. Here, we show that functional loss of GD-linked glucocerebrosidase (GCase) in primary cultures or human iPS neurons compromises lysosomal protein degradation, causes accumulation of α-synuclein (α-syn), and results in neurotoxicity through aggregation-dependent mechanisms. Glucosylceramide (GlcCer), the GCase substrate, directly influenced amyloid formation of purified α-syn by stabilizing soluble oligomeric intermediates. We further demonstrate that α-syn inhibits the lysosomal activity of normal GCase in neurons and idiopathic PD brain, suggesting that GCase depletion contributes to the pathogenesis of sporadic synucleinopathies. These findings suggest that the bidirectional effect of α-syn and GCase forms a positive feedback loop that may lead to a self-propagating disease. Therefore, improved targeting of GCase to lysosomes may represent a specific therapeutic approach for PD and other synucleinopathies.
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SMPD1 encodes for acid-sphingomyelinase and has been identified in several PD risk GWAS and confirmatory studies; moreover, reduced acid-sphingomyelinase activity correlates with earlier age of onset of PD.
“SMPD1 encodes for acid-sphingomyelinase and has been identified in several PD risk GWAS and confirmatory studies; moreover, reduced acid-sphingomyelinase activity correlates with earlier age of onset of PD.107”
From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [107]
The Introduction discusses GBA1 and glucocerebrosidase as a genetic risk factor and enzyme relevant to Parkinson’s disease, and the Results report reduced glucocerebrosidase activity in PD brain; neither passage addresses SMPD1 or acid-sphingomyelinase. Searches for SMPD1, acid-sphingomyelinase, GWAS, and age of PD onset found no passage supporting the attributed claim. (LLM, conf=0.76)
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- Authors
- Mazzulli, J. R., Xu, Y.-H., Sun, Y., Knight, A. L., McLean, P. J., Caldwell, G. A., Sidransky, E., Grabowski, G. A., & Krainc, D.
- Affiliations
- Harvard University (US)
- Cincinnati Children's Hospital Medical Center (US)
- University of Alabama (US)
- National Institutes of Health (US)
- Corresponding author
- Krainc, Dimitri
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2011-07
- Volume
- 146
- Issue
- 1
- Pages
- 37-52
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3132082
- OpenAlex
- W2031365272
- Cited by
- 1,341
- References
- 3
- Citations by year
- 2026: 88 · 2025: 97 · 2024: 98 · 2023: 67 · 2022: 108 · 2021: 112 · 2020: 108 · 2019: 99 · 2018: 92 · 2017: 81 · 2016: 83 · 2015: 86 · 2014: 65 · 2013: 84 · 2012: 54
- FWCI
- 45.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 747 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Human Genome Research Institute (ZIAHG200336)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK036729, R01DK36729)
- National Institute of Neurological Disorders and Stroke (F32NS066730, R01NS070168, R01NS051303)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
- Keywords
- Gaucher disease, glucocerebrosidase, alpha-synuclein, Parkinson's disease, synucleinopathies, lysosomal storage disease, lysosomal protein degradation, protein aggregation, glucosylceramide, amyloid fibril formation, neurotoxicity, positive feedback loop
- MeSH terms
- Animals, Brain, Cells, Cultured, Disease Models, Animal, Gaucher Disease, Glucosylceramidase, Glucosylceramides, Humans, Lysosomes, Neurons, Feedback, Physiological, Mice, alpha-Synuclein
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