期刊
BRAIN
卷 142, 期 -, 页码 2845-2859出版社
OXFORD UNIV PRESS
DOI: 10.1093/brain/awz205
关键词
Parkinson's disease; alpha-synuclein; arylsulfatase A; molecular chaperone; protein aggregation and propagation
资金
- National Research Foundation of Korea (NRF) - Korean Government (MSIT) [NRF-2018R1A2A1A05078261, NRF-2018R1A5A2025964]
- Seoul National University Hospital
- National Health and Medical Research Council of Australia (NHMRC)
- BK21-Plus education program
Mutations in lysosomal genes increase the risk of neurodegenerative diseases, as is the case for Parkinson's disease. Here, we found that pathogenic and protective mutations in arylsulfatase A (ARSA), a gene responsible for metachromatic leukodystrophy, a lysosomal storage disorder, are linked to Parkinson's disease. Plasma ARSA protein levels were changed in Parkinson's disease patients. ARSA deficiency caused increases in alpha-synuclein aggregation and secretion, and increases in alpha-synuclein propagation in cells and nematodes. Despite being a lysosomal protein, ARSA directly interacts with alpha-synuclein in the cytosol. The interaction was more extensive with protective ARSA variant and less with pathogenic ARSA variant than wild-type. ARSA inhibited the in vitro fibrillation of alpha-synuclein in a dose-dependent manner. Ectopic expression of ARSA reversed the alpha-synuclein phenotypes in both cell and fly models of synucleinopathy, the effects correlating with the extent of the physical interaction between these molecules. Collectively, these results suggest that ARSA is a genetic modifier of Parkinson's disease pathogenesis, acting as a molecular chaperone for alpha-synuclein.
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