Abstract
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.
Original language | English (US) |
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Pages (from-to) | 37-52 |
Number of pages | 16 |
Journal | Cell |
Volume | 146 |
Issue number | 1 |
DOIs | |
State | Published - Jul 8 2011 |
Funding
We thank Harry Ischiropoulos for pCDNA3.1 human α-syn plasmids and syn303 antibody, Benoit I. Giasson for the SNL-1 antibody, and Kimberly Kegel for technical advice on liposome formation. This work was supported by National Institutes of Health grants R01NS051303 (D.K.) and F32NS066730 (J.R.M.) from the National Institute of Neurological Disorders and Stroke, R01DK36729 (G.A.G.), and the Intramural Programs of the National Human Genome Research Institute and the National Institutes of Health (E.S.).
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology