期刊
NATURE NEUROSCIENCE
卷 16, 期 4, 页码 394-U52出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nn.3350
关键词
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资金
- US National Institutes of Health National Institute on Aging [AG031782, AG038072, AG08702, T32AG023475]
- MINECO [SAF2012-33526, PLE2009-0144, ACI2010-1117, RyC-2008-02772, BFU2010-21823]
- Beatrice and Roy Backus Foundation
- Rainwaters Foundation
- Robert and Renee Belfer gift
- JPB Foundation
- Parkinson's Disease Foundation
- Fondazione Guido Berlucchi
- CIBERNED Cooperative Project
- US National Institute of Neurological Disorders and Stroke Udall Center of Excellence
- Hirschl/Weill-Caulier Career Scientist Award
- American Academy of Neurology Research Fellowship
- ICREA Funding Source: Custom
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease. We found LRRK2 to be degraded in lysosomes by chaperone-mediated autophagy (CMA), whereas the most common pathogenic mutant form of LRRK2, G2019S, was poorly degraded by this pathway. In contrast to the behavior of typical CMA substrates, lysosomal binding of both wild-type and several pathogenic mutant LRRK2 proteins was enhanced in the presence of other CMA substrates, which interfered with the organization of the CMA translocation complex, resulting in defective CMA. Cells responded to such LRRK2-mediated CMA compromise by increasing levels of the CMA lysosomal receptor, as seen in neuronal cultures and brains of LRRK2 transgenic mice, induced pluripotent stem cell-derived dopaminergic neurons and brains of Parkinson's disease patients with LRRK2 mutations. This newly described LRRK2 self-perpetuating inhibitory effect on CMA could underlie toxicity in Parkinson's disease by compromising the degradation of alpha-synuclein, another Parkinson's disease-related protein degraded by this pathway.
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