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Variants in saposin D domain of prosaposin gene linked to Parkinson's disease.
Brain ( IF 14.5 ) Pub Date : 2020-04-01 , DOI: 10.1093/brain/awaa064 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 ( IF 14.5 ) Pub Date : 2020-04-01 , DOI: 10.1093/brain/awaa064 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
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.
更新日期：2020-04-21
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