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

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 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.

• Authors: 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
• Journal: Brain : a journal of neurology (Brain) Vol. 143 Issue 4 Pg. 1190-1205 (04 01 2020) ISSN: 1460-2156 [Electronic] England
• PMID: 32201884 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: [email protected].

Chemical References

• PSAP protein, human
• Psap protein, mouse
• Saposins

Topics

• Aged
• Animals
• Case-Control Studies
• Dopaminergic Neurons (pathology)
• Female
• Genetic Predisposition to Disease (genetics)
• Humans
• Male
• Mice
• Mice, Mutant Strains
• Middle Aged
• Nerve Degeneration (genetics, pathology)
• Parkinson Disease (genetics, pathology)
• Saposins (genetics)