Arylsulfatase A, a genetic modifier of Parkinson's disease, is an ?-synuclein chaperone.

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 ?-synuclein aggregation and secretion, and increases in ?-synuclein propagation in cells and nematodes. Despite being a lysosomal protein, ARSA directly interacts with ?-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 ?-synuclein in a dose-dependent manner. Ectopic expression of ARSA reversed the ?-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 ?-synuclein.
Mesh Terms:
Adult, Aged, Animals, Animals, Genetically Modified, Brain, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Cells, Cultured, Cerebroside-Sulfatase, Dementia, Drosophila Proteins, Drosophila melanogaster, Female, Gene Knockout Techniques, Genes, Dominant, Humans, Male, Middle Aged, Molecular Chaperones, Mutation, Missense, Parkinson Disease, Pedigree, Point Mutation, Protein Aggregation, Pathological, Protein Interaction Mapping, Recombinant Proteins, alpha-Synuclein
Brain
Date: Dec. 01, 2018
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