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Brain, Published: 15 July 2019 | https://doi.org/10.1093/brain/awz205 Arylsulfatase A, a genetic modifier of Parkinson’s disease, is an α-synuclein chaperone

Jun Sung Lee,^1,*Kazuaki Kanai,²Mari Suzuki,^3,4 Woojin S. Kim,⁵ Han Soo Yoo,⁶ YuHong Fu,⁵Dong-Kyu Kim,¹ Byung Chul Jung,¹ Minsun Choi,¹ Kyu Won Oh,¹ Yuanzhe Li,² Mitsuyoshi Nakatani,²Tomoko Nakazato,² Satoko Sekimoto,² Manabu Funayama,² Hiroyo Yoshino,² Shin-ichiro Kubo,²Kenya Nishioka,²Ryusuke Sakai,^4,7 Morio Ueyama,⁴ Hideki Mochizuki,⁷ He-Jin Lee,⁸ Sergio Pablo Sardi,⁹ Glenda M. Halliday,⁵Yoshitaka Nagai,^4,7 Phil Hyu Lee,⁶ Nobutaka Hattori² and Seung-Jae Lee ¹

¹Department of Biomedical Sciences, Neuroscience Research Institute, and Department of Medicine, Seoul National University College of Medicine, Seoul 03080, Korea
² Department of Neurology, Juntendo University, School of Medicine, Tokyo 113–8421, Japan
³ Diabetic Neuropathy Project, Department of Sensory and Motor Systems, Tokyo Metropolitan Institute of Medical Science, Tokyo 156–8506, Japan
⁴ Department of Neurotherapeutics, Osaka University Graduate School of Medicine, Osaka 565–0871, Japan
⁵ Brain and Mind Centre, Sydney Medical School, The University of Sydney, Camperdown, NSW 2050, Australia
⁶ Department of Neurology, Yonsei University College of Medicine, Seoul 03722, Korea
⁷ Department of Neurology, Osaka University Graduate School of Medicine, Osaka 565–0871, Japan
⁸ Departmen of Anatomy, School of Medicine, Konkuk University, Seoul 05029, Korea
⁹ Genzyme, a Sanofi Company, Framingham, Massachusetts 01701, USA

^*Present address: Neuramedy Co., Ltd., Seoul National University College of Medicine, Convergence building, Rm 408, Daehak-ro 103, Jongro-gu, Seoul 03080, Korea

Correspondence to: Prof. Seung-Jae Lee, Seoul National University College of Medicine, Convergence building, Rm 402, Daehak-ro 103, Jongro-gu, Seoul 03080, Korea

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.

Keywords: Parkinson’s disease, α-synuclein, arylsulfatase A, molecular chaperone, protein aggregation and propagation

논문정보

TOP52019년 선정

형식Research article
게재일2019년 07월 (BRIC 등록일 2019-08-12)
연구진국내(교신)+국외 연구진
분야 의약학 > 신경의학

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