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

Brain. 2020 Apr 1;143(4):1190-1205. doi: 10.1093/brain/awaa064.

Yutaka Oji ¹, Taku Hatano ¹, Shin-Ichi Ueno ¹, Manabu Funayama ², Kei-Ichi Ishikawa ¹ ³, Ayami Okuzumi ¹, Sachiko Noda ¹, Shigeto Sato ¹, Wataru Satake ⁴, Tatsushi Toda ⁴, Yuanzhe Li ¹, Tomoko Hino-Takai ⁵, Soichiro Kakuta ⁶, Taiji Tsunemi ¹, Hiroyo Yoshino ², Kenya Nishioka ¹, Tatsuya Hattori ⁷, Yasuaki Mizutani ⁸, Tatsuro Mutoh ⁸, Fusako Yokochi ⁹, Yuta Ichinose ¹⁰, Kishin Koh ¹⁰, Kazumasa Shindo ¹⁰, Yoshihisa Takiyama ¹⁰, Tsuyoshi Hamaguchi ¹¹, Masahito Yamada ¹¹, Matthew J Farrer ¹² ¹³, Yasuo Uchiyama ¹⁴, Wado Akamatsu ³, Yih-Ru Wu ¹⁵, Junko Matsuda ⁵, Nobutaka Hattori ¹

Affiliations

1 Department of Neurology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
2 Research Institute for Diseases of Old Age, Juntendo University Graduate School of Medicine, Tokyo, Japan.
3 Center for Genomic and Regenerative Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
4 Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
5 Department of Pathophysiology and Metabolism, Kawasaki Medical School, Okayama, Japan.
6 Laboratory of Morphology and Image Analysis, Research Support Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
7 Department of Neurology, Hommachi Neurological Clinic, Nagoya, Japan.
8 Department of Neurology, Fujita Health University School of Medicine, Aichi, Japan.
9 Department of Neurology, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan.
10 Department of Neurology, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, Japan.
11 Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
12 Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
13 Department of Neurology, University of Florida, Gainesville, USA.
14 Department of Cellular and Molecular Neuropathology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
15 Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan.

PMID: 32201884 DOI: 10.1093/brain/awaa064

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.

Keywords

Parkinson’s disease; lysosomal storage disorder; prosaposin; saposin D; α-synuclein.

Name
Email *

	Sorry, but the email address you supplied was invalid.