Variants in saposin D domain of prosaposin gene linked to Parkinson's disease.
Yutaka Oji, Taku Hatano, Shin-Ichi Ueno, Manabu Funayama, Kei-Ichi Ishikawa, Ayami Okuzumi, Sachiko Noda, Shigeto Sato, Wataru Satake, Tatsushi Toda, Yuanzhe Li, Tomoko Hino-Takai, Soichiro Kakuta, Taiji Tsunemi, Hiroyo Yoshino, Kenya Nishioka, Tatsuya Hattori, Yasuaki Mizutani, Tatsuro Mutoh, Fusako Yokochi, Yuta Ichinose, Kishin Koh, Kazumasa Shindo, Yoshihisa Takiyama, Tsuyoshi Hamaguchi, Masahito Yamada, Matthew J Farrer, Yasuo Uchiyama, Wado Akamatsu, Yih-Ru Wu, Junko Matsuda, Nobutaka Hattori
Brain : a journal of neurology 2020 Apr 01Recently, the genetic variability in lysosomal storage disorders has been implicated in the pathogenesis of Parkinson's disease. Here, we found that variants in prosaposin (PSAP), a rare causative gene of various types of lysosomal storage disorders, are linked to Parkinson's disease. Genetic mutation screening revealed three pathogenic mutations in the saposin D domain of PSAP from three families with autosomal dominant Parkinson's disease. Whole-exome sequencing revealed no other variants in previously identified Parkinson's disease-causing or lysosomal storage disorder-causing genes. A case-control association study found two variants in the intronic regions of the PSAP saposin D domain (rs4747203 and rs885828) in sporadic Parkinson's disease had significantly higher allele frequencies in a combined cohort of Japan and Taiwan. We found the abnormal accumulation of autophagic vacuoles, impaired autophagic flux, altered intracellular localization of prosaposin, and an aggregation of α-synuclein in patient-derived skin fibroblasts or induced pluripotent stem cell-derived dopaminergic neurons. In mice, a Psap saposin D mutation caused progressive motor decline and dopaminergic neurodegeneration. Our data provide novel genetic evidence for the involvement of the PSAP saposin D domain in Parkinson's disease. © The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.
Citation
Yutaka Oji, Taku Hatano, Shin-Ichi Ueno, Manabu Funayama, Kei-Ichi Ishikawa, Ayami Okuzumi, Sachiko Noda, Shigeto Sato, Wataru Satake, Tatsushi Toda, Yuanzhe Li, Tomoko Hino-Takai, Soichiro Kakuta, Taiji Tsunemi, Hiroyo Yoshino, Kenya Nishioka, Tatsuya Hattori, Yasuaki Mizutani, Tatsuro Mutoh, Fusako Yokochi, Yuta Ichinose, Kishin Koh, Kazumasa Shindo, Yoshihisa Takiyama, Tsuyoshi Hamaguchi, Masahito Yamada, Matthew J Farrer, Yasuo Uchiyama, Wado Akamatsu, Yih-Ru Wu, Junko Matsuda, Nobutaka Hattori. Variants in saposin D domain of prosaposin gene linked to Parkinson's disease. Brain : a journal of neurology. 2020 Apr 01;143(4):1190-1205
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PMID: 32201884
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