Arylsulfatase A, a genetic modifier of Parkinson’s disease, is an α-synuclein chaperone

Jun Sung Lee, Kazuaki Kanai, Mari Suzuki, Woojin S. Kim, Han Soo Yoo, Yu Hong Fu, Dong Kyu Kim, Byung Chul Jung, Minsun Choi, Kyu Won Oh, Yuanzhe Li, Mitsuyoshi Nakatani, Tomoko Nakazato, Satoko Sekimoto, Manabu Funayama, Hiroyo Yoshino, Shin ichiro Kubo, Kenya Nishioka, Ryusuke Sakai, Morio UeyamaHideki Mochizuki, He Jin Lee, Sergio Pablo Sardi, Glenda M. Halliday, Yoshitaka Nagai, Phil Hyu Lee, Nobutaka Hattori, Seung Jae Lee

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2845-2859
Number of pages15
JournalBrain
Volume142
Issue number9
DOIs
Publication statusPublished - 2019 Sep 1

All Science Journal Classification (ASJC) codes

  • Clinical Neurology

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    Lee, J. S., Kanai, K., Suzuki, M., Kim, W. S., Yoo, H. S., Fu, Y. H., Kim, D. K., Jung, B. C., Choi, M., Oh, K. W., Li, Y., Nakatani, M., Nakazato, T., Sekimoto, S., Funayama, M., Yoshino, H., Kubo, S. I., Nishioka, K., Sakai, R., ... Lee, S. J. (2019). Arylsulfatase A, a genetic modifier of Parkinson’s disease, is an α-synuclein chaperone. Brain, 142(9), 2845-2859. https://doi.org/10.1093/brain/awz205