Regulation of the VHL/HIF-1 pathway by DJ-1

J Neurosci. 2014 Jun 4;34(23):8043-50. doi: 10.1523/JNEUROSCI.1244-13.2014.

Abstract

DJ-1 (PARK7) is a gene linked to autosomal recessive Parkinson disease (PD). We showed previously that DJ-1 loss sensitizes neurons in models of PD and stroke. However, the biochemical mechanisms underlying this protective role are not completely clear. Here, we identify Von Hippel Lindau (VHL) protein as a critical DJ-1-interacting protein. We provide evidence that DJ-1 negatively regulates VHL ubiquitination activity of the α-subunit of hypoxia-inducible factor-1 (HIF-1α) by inhibiting HIF-VHL interaction. Consistent with this observation, DJ-1 deficiency leads to lowered HIF-1α levels in models of both hypoxia and oxidative stress, two stresses known to stabilize HIF-1α. We also demonstrate that HIF-1α accumulation rescues DJ-1-deficient neurons against 1-methyl-4-phenylpyridinium-induced toxicity. Interestingly, lymphoblast cells extracted from DJ-1-related PD patients show impaired HIF-1α stabilization when compared with normal individuals, indicating that the DJ-1-VHL link may also be relevant to a human context. Together, our findings delineate a model by which DJ-1 mediates neuronal survival by regulation of the VHL-HIF-1α pathway.

Keywords: DJ-1; Parkinson's disease; oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / pharmacology
  • Animals
  • Cells, Cultured
  • Embryo, Mammalian
  • Female
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Neuroblastoma / pathology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Neurotoxins / pharmacology
  • Oncogene Proteins / deficiency
  • Oncogene Proteins / metabolism*
  • Oxidative Stress / drug effects
  • Oxidative Stress / genetics
  • Parkinson Disease / pathology
  • Peroxiredoxins
  • Protein Deglycase DJ-1
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Time Factors
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics
  • Von Hippel-Lindau Tumor Suppressor Protein / metabolism*

Substances

  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Neurotoxins
  • Oncogene Proteins
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Peroxiredoxins
  • Von Hippel-Lindau Tumor Suppressor Protein
  • PARK7 protein, mouse
  • Protein Deglycase DJ-1