Variants in saposin D domain of prosaposin gene linked to Parkinson’s disease
| Autor: | Tatsuro Mutoh, Shigeto Sato, Yuanzhe Li, Taiji Tsunemi, Taku Hatano, Kishin Koh, Yasuo Uchiyama, Soichiro Kakuta, Tatsuya Hattori, Wado Akamatsu, Yoshihisa Takiyama, Yuta Ichinose, Tomoko Hino-Takai, Junko Matsuda, Matthew J. Farrer, Kenya Nishioka, Wataru Satake, Manabu Funayama, Sachiko Noda, Yasuaki Mizutani, Kei-Ichi Ishikawa, Tatsushi Toda, Yutaka Oji, Nobutaka Hattori, Hiroyo Yoshino, Masahito Yamada, Tsuyoshi Hamaguchi, Ayami Okuzumi, Shin Ichi Ueno, Kazumasa Shindo, Yih Ru Wu, Fusako Yokochi |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Genetics Prosaposin Mutation Parkinson's disease Dopaminergic Neurodegeneration Biology medicine.disease_cause medicine.disease Pathogenesis 03 medical and health sciences 030104 developmental biology 0302 clinical medicine medicine Neurology (clinical) Gene Allele frequency 030217 neurology & neurosurgery |
| Zdroj: | Brain. 143:1190-1205 |
| ISSN: | 1460-2156 0006-8950 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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