@article{70c5df1ea05846f4b386e1cc28836be5,
title = "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 a-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.",
author = "Yutaka Oji and Taku Hatano and Ueno, {Shin Ichi} and Manabu Funayama and Ishikawa, {Kei Ichi} and Ayami Okuzumi and Sachiko Noda and Shigeto Sato and Wataru Satake and Tatsushi Toda and Yuanzhe Li and Tomoko Hino-Takai and Soichiro Kakuta and Taiji Tsunemi and Hiroyo Yoshino and Kenya Nishioka and Tatsuya Hattori and Yasuaki Mizutani and Tatsuro Mutoh and Fusako Yokochi and Yuta Ichinose and Kishin Koh and Kazumasa Shindo and Yoshihisa Takiyama and Tsuyoshi Hamaguchi and Masahito Yamada and Farrer, {Matthew J.} and Yasuo Uchiyama and Wado Akamatsu and Wu, {Yih Ru} and Junko Matsuda and Nobutaka Hattori",
note = "Funding Information: We thank all the patients who participated in the study, and their families. We thank Takashi Ogawa, Mana Yamakawa, Tomoko Nihira-Funayama, Norihiko Furuya, and Kazuaki Kanai for clinical examinations and technical assistance. We thank Bronwen Gardner, PhD, and Melony Black, PhD, from Edanz Group (www.edanzediting.com/ac) for editing drafts of this manuscript. This study was supported by Supported Program for the Strategic Research Foundation at Private Universities, and Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Numbers JP16H07184 (to Y.O.), JP19K17019 (to Y.O.), JP25461290 (to T.Hata.), JP24390224 (to N.H.), and JP18H04043 (to N.H.). This work was also supported by Japan Agency for Medical Research and Development (AMED); Advanced Research & Development Programs for Medical Innovation (AMED-CREST) (to N.H.), Strategic Research Program for Brain Sciences (to T.Hata.),18bm0804003 and 19bm0804003 (to W.A. and N.H.), 18km0405206 and 19km0405206 (to T.To. and N.H.), 19dm0107156 (to T.Hata.), 19ek0109358 (to N.H.), 19ek0109393 (to N.H.), and 19dm0207070 (to N.H.). This study was also supported by the Grants-in Aid from the Research Committee of CNS Degenerative Disease, Research on Policy Planning and Evaluation for Rare and Intractable Diseases, Health, Labour and Welfare Sciences Research Grants, and the Ministry of Health, Labour and Welfare, Japan (to N.H.). M.J.F. received support from the Canadian Institutes of Health Operating Grant (FRN 123275). Y.R.W. received support from Minister of Science and Technology, Taiwan (MOST 107-2314-B-182A-045-MY2) and Chang Gung Memorial Hospital, Taipei, Taiwan (CMRPG3H0313).",
year = "2020",
month = mar,
day = "1",
doi = "10.1093/brain/awaa064",
language = "English",
volume = "143",
pages = "1190--1205",
journal = "Brain",
issn = "0006-8950",
publisher = "Oxford University Press",
number = "3",
}