DJ-1 deficiency impairs glutamate uptake into astrocytes via the regulation of flotillin-1 and caveolin-1 expression

Sci Rep. 2016 Jun 27;6:28823. doi: 10.1038/srep28823.

Abstract

Parkinson's disease (PD) is a common chronic and progressive neurodegenerative disorder. Although the cause of PD is still poorly understood, mutations in many genes including SNCA, parkin, PINK1, LRRK2, and DJ-1 have been identified in the familial forms of PD. It was recently proposed that alterations in lipid rafts may cause the neurodegeneration shown in PD. Here, we observe that DJ-1 deficiency decreased the expression of flotillin-1 (flot-1) and caveolin-1 (cav-1), the main protein components of lipid rafts, in primary astrocytes and MEF cells. As a mechanism, DJ-1 regulated flot-1 stability by direct interaction, however, decreased cav-1 expression may not be a direct effect of DJ-1, but rather as a result of decreased flot-1 expression. Dysregulation of flot-1 and cav-1 by DJ-1 deficiency caused an alteration in the cellular cholesterol level, membrane fluidity, and alteration in lipid rafts-dependent endocytosis. Moreover, DJ-1 deficiency impaired glutamate uptake into astrocytes, a major function of astrocytes in the maintenance of CNS homeostasis, by altering EAAT2 expression. This study will be helpful to understand the role of DJ-1 in the pathogenesis of PD, and the modulation of lipid rafts through the regulation of flot-1 or cav-1 may be a novel therapeutic target for PD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / metabolism*
  • Brain / pathology
  • Caveolin 1 / metabolism*
  • Central Nervous System
  • Cholesterol / metabolism
  • Endocytosis
  • Excitatory Amino Acid Transporter 2 / metabolism
  • Gene Expression Regulation
  • Glutamic Acid / metabolism*
  • Glutamic Acid / pharmacokinetics
  • Homeostasis
  • Membrane Microdomains
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Mutation
  • Protein Binding
  • Protein Deglycase DJ-1 / deficiency*
  • Protein Deglycase DJ-1 / genetics*

Substances

  • Caveolin 1
  • Excitatory Amino Acid Transporter 2
  • Membrane Proteins
  • Slc1a2 protein, mouse
  • flotillins
  • Glutamic Acid
  • Cholesterol
  • PARK7 protein, mouse
  • Protein Deglycase DJ-1