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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Case-Control Studies
  • Dopaminergic Neurons / pathology
  • Female
  • Genetic Predisposition to Disease / genetics*
  • Humans
  • Male
  • Mice
  • Mice, Mutant Strains
  • Middle Aged
  • Nerve Degeneration / genetics
  • Nerve Degeneration / pathology
  • Parkinson Disease / genetics*
  • Parkinson Disease / pathology
  • Saposins / genetics*

Substances

  • PSAP protein, human
  • Psap protein, mouse
  • Saposins