論文

査読有り 国際誌
2020年3月23日

Variants in saposin D domain of prosaposin gene linked to Parkinson's disease.

Brain : a journal of neurology
  • 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
  • 全て表示

記述言語
英語
掲載種別
DOI
10.1093/brain/awaa064

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 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.

リンク情報
DOI
https://doi.org/10.1093/brain/awaa064
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/32201884
ID情報
  • DOI : 10.1093/brain/awaa064
  • PubMed ID : 32201884

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