Variants in saposin D domain of prosaposin gene linked to Parkinson’s disease
Open accessAbstract
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.
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From Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis (2021) · cites this paper as [32]
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Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis
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Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis
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- Authors
- Oji, Y., Hatano, T., Ueno, S.-I., Funayama, M., Ishikawa, K.-I., Okuzumi, A., Noda, S., Sato, S., Satake, W., Toda, T., Li, Y., Hino-Takai, T., Kakuta, S., Tsunemi, T., Yoshino, H., Nishioka, K., Hattori, T., Mizutani, Y., Mutoh, T., Yokochi, F., Ichinose, Y., Koh, K., Shindo, K., Takiyama, Y., Hamaguchi, T., Yamada, M., Farrer, M. J., Uchiyama, Y., Akamatsu, W., Wu, Y.-R., Matsuda, J., & Hattori, N.
- Affiliations
- Juntendo University (JP)
- The University of Tokyo (JP)
- Kawasaki Medical School (JP)
- Department of Neurology, Hommachi Neurological Clinic, Nagoya, Japan
- Fujita Health University (JP)
- Tokyo Metropolitan Neurological Hospital (JP)
- University of Yamanashi (JP)
- Kanazawa University (JP)
- University of British Columbia (CA)
- Chang Gung University (TW)
- Corresponding author
- Hattori, Nobutaka
- ORCID
- Oji, Yutaka
- Hatano, Taku
- Funayama, Manabu
- Ishikawa, Kei-ichi
- Okuzumi, Ayami
- Sato, Shigeto
- Satake, Wataru
- Toda, Tatsushi
- Kakuta, Soichiro
- Tsunemi, Taiji
- Yoshino, Hiroyo
- Nishioka, Kenya
- Hattori, Tatsuya
- Mizutani, Yasuaki
- Mutoh, Tatsuro
- Yokochi, Fusako
- Ichinose, Yuta
- Koh, Kishin
- Shindo, Kazumasa
- Takiyama, Yoshihisa
- Hamaguchi, Tsuyoshi
- Yamada, Masahito
- Farrer, Matthew J
- Uchiyama, Yasuo
- Akamatsu, Wado
- Wu, Yih-Ru
- Matsuda, Junko
- Hattori, Nobutaka
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2020-03-23
- Volume
- 143
- Issue
- 4
- Pages
- 1190-1205
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- OpenAlex
- W3012573239
- Cited by
- 116
- References
- 61
- Citations by year
- 2026: 18 · 2025: 15 · 2024: 16 · 2023: 15 · 2022: 18 · 2021: 18 · 2020: 15
- FWCI
- 7.14
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Brain (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Strategic Research Foundation at Private Universities
- Japan Society for the Promotion of Science
- KAKENHI (JP16H07184, JP19K17019, JP25461290, JP24390224, JP18H04043)
- Japan Agency for Medical Research and Development
- Advanced Research & Development Programs for Medical Innovation
- Strategic Research Program for Brain Sciences (18bm0804003, 19bm0804003, 18km0405206, 19km0405206, 19dm0107156, 19ek0109358, 19ek0109393, 19dm0207070)
- Grants-in Aid from the Research Committee of CNS Degenerative Disease
- Research on Policy Planning and Evaluation for Rare and Intractable Diseases, Health, Labour
- Welfare Sciences Research Grants
- Ministry of Health, Labour and Welfare
- Canadian Institutes of Health Operating Grant (FRN 123275)
- Minister of Science and Technology (MOST 107-2314-B-182A-045-MY2)
- Chang Gung Memorial Hospital (CMRPG3H0313)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Keywords
- Parkinson's disease, prosaposin, lysosomal storage disease, genetic variants, autosomal dominant Parkinson's disease, sporadic Parkinson's disease, autophagic flux, autophagosomes, alpha-synuclein aggregation, dopaminergic neuron loss, motor function decline, genetic association
- MeSH terms
- Aged, Animals, Female, Humans, Male, Mice, Mutant Strains, Middle Aged, Nerve Degeneration, Parkinson Disease, Case-Control Studies, Genetic Predisposition to Disease, Saposins, Mice, Dopaminergic Neurons
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