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 YokochiYuta 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

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

Abstract

Recently, 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 a-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.

Original languageEnglish
Pages (from-to)1190-1205
Number of pages16
JournalBrain
Volume143
Issue number3
DOIs
Publication statusPublished - 01-03-2020

All Science Journal Classification (ASJC) codes

  • Clinical Neurology

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