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Here, we found that variants in prosaposin (PSAP), a rare causative gene of various types of lysosomal storage disorders, are linked to Parkinson\u2019s disease. Genetic mutation screening revealed three pathogenic mutations in the saposin D domain of PSAP from three families with autosomal dominant Parkinson\u2019s disease. Whole-exome sequencing revealed no other variants in previously identified Parkinson\u2019s 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\u2019s 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 \u03b1-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\u2019s disease.<\/jats:p>","DOI":"10.1093\/brain\/awaa064","type":"journal-article","created":{"date-parts":[[2020,2,20]],"date-time":"2020-02-20T07:44:53Z","timestamp":1582184693000},"page":"1190-1205","source":"Crossref","is-referenced-by-count":115,"title":["Variants in saposin D domain of prosaposin gene linked to Parkinson\u2019s disease"],"prefix":"10.1093","volume":"143","author":[{"given":"Yutaka","family":"Oji","sequence":"first","affiliation":[{"name":"Department of Neurology, Juntendo University Graduate School of Medicine, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taku","family":"Hatano","sequence":"first","affiliation":[{"name":"Department of Neurology, Juntendo University Graduate School of Medicine, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin-Ichi","family":"Ueno","sequence":"first","affiliation":[{"name":"Department of Neurology, Juntendo University Graduate School of Medicine, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manabu","family":"Funayama","sequence":"first","affiliation":[{"name":"Research Institute for Diseases of Old Age, Juntendo University Graduate School of Medicine, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kei-ichi","family":"Ishikawa","sequence":"first","affiliation":[{"name":"Department of Neurology, Juntendo University Graduate School of Medicine, Tokyo, Japan"},{"name":"Center for Genomic and Regenerative Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayami","family":"Okuzumi","sequence":"first","affiliation":[{"name":"Department of Neurology, Juntendo University 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Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanzhe","family":"Li","sequence":"first","affiliation":[{"name":"Department of Neurology, Juntendo University Graduate School of Medicine, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoko","family":"Hino-Takai","sequence":"first","affiliation":[{"name":"Department of Pathophysiology and Metabolism, Kawasaki Medical School, Okayama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soichiro","family":"Kakuta","sequence":"first","affiliation":[{"name":"Laboratory of Morphology and Image Analysis, Research Support Center, Juntendo University Graduate School of Medicine, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taiji","family":"Tsunemi","sequence":"first","affiliation":[{"name":"Department of Neurology, Juntendo University Graduate School of Medicine, Tokyo, 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Kanazawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J","family":"Farrer","sequence":"first","affiliation":[{"name":"Department of Medical Genetics, University of British Columbia, Vancouver, Canada"},{"name":"Department of Neurology, University of Florida, Gainesville, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuo","family":"Uchiyama","sequence":"first","affiliation":[{"name":"Department of Cellular and Molecular Neuropathology, Juntendo University Graduate School of Medicine, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wado","family":"Akamatsu","sequence":"first","affiliation":[{"name":"Center for Genomic and Regenerative Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yih-Ru","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Neurology, Chang Gung Memorial Hospital, Chang Gung 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