Arylsulfatase A, a genetic modifier of Parkinson’s disease, is an α-synuclein chaperone
| Autor: | Mari Suzuki, Byung Chul Jung, Kenya Nishioka, Yuanzhe Li, Phil Hyu Lee, He Jin Lee, Nobutaka Hattori, Minsun Choi, Hideki Mochizuki, Seung-Jae Lee, Dong Kyu Kim, YuHong Fu, Han Soo Yoo, Ryusuke Sakai, Yoshitaka Nagai, Mitsuyoshi Nakatani, Woojin S. Kim, Glenda M. Halliday, Manabu Funayama, Tomoko Nakazato, Morio Ueyama, Sergio Pablo Sardi, Jun Sung Lee, Hiroyo Yoshino, Satoko Sekimoto, Kyu Won Oh, Shin Ichiro Kubo, Kazuaki Kanai |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Arylsulfatase A Parkinson's disease Cerebroside-sulfatase Biology Protein aggregation medicine.disease Phenotype nervous system diseases Cell biology Metachromatic leukodystrophy 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Chaperone (protein) medicine biology.protein Ectopic expression Neurology (clinical) 030217 neurology & neurosurgery |
| Zdroj: | Brain. 142:2845-2859 |
| ISSN: | 1460-2156 0006-8950 |
| Popis: | 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 α-synuclein aggregation and secretion, and increases in α-synuclein propagation in cells and nematodes. Despite being a lysosomal protein, ARSA directly interacts with α-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 α-synuclein in a dose-dependent manner. Ectopic expression of ARSA reversed the α-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 α-synuclein. |
| Databáze: | OpenAIRE |
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