DJ-1 deficiency impairs synaptic vesicle endocytosis and reavailability at nerve terminals

Proc Natl Acad Sci U S A. 2018 Feb 13;115(7):1629-1634. doi: 10.1073/pnas.1708754115. Epub 2018 Jan 31.

Abstract

Mutations in DJ-1 (PARK7) are a known cause of early-onset autosomal recessive Parkinson's disease (PD). Accumulating evidence indicates that abnormalities of synaptic vesicle trafficking underlie the pathophysiological mechanism of PD. In the present study, we explored whether DJ-1 is involved in CNS synaptic function. DJ-1 deficiency impaired synaptic vesicle endocytosis and reavailability without inducing structural alterations in synapses. Familial mutants of DJ-1 (M26I, E64D, and L166P) were unable to rescue defective endocytosis of synaptic vesicles, whereas WT DJ-1 expression completely restored endocytic function in DJ-1 KO neurons. The defective synaptic endocytosis shown in DJ-1 KO neurons may be attributable to alterations in membrane cholesterol level. Thus, DJ-1 appears essential for synaptic vesicle endocytosis and reavailability, and impairment of this function by familial mutants of DJ-1 may be related to the pathogenesis of PD.

Keywords: DJ-1; Parkinson’s disease; synaptic vesicle endocytosis; synaptic vesicle reavailability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Endocytosis / physiology*
  • Mice
  • Mice, Knockout
  • Mutation
  • Nerve Endings / metabolism
  • Nerve Endings / pathology*
  • Protein Deglycase DJ-1 / physiology*
  • Synapses / metabolism
  • Synapses / pathology*
  • Synaptic Vesicles / metabolism
  • Synaptic Vesicles / pathology*

Substances

  • PARK7 protein, mouse
  • Protein Deglycase DJ-1