4.7 Article

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

Journal

JOURNAL OF NEUROSCIENCE
Volume 34, Issue 23, Pages 8043-8050

Publisher

SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1244-13.2014

Keywords

DJ-1; oxidative stress; Parkinson's disease

Categories

Funding

  1. Canadian Institutes of Health Research, Heart and Stroke Foundation of Ontario
  2. Parkinson's Society Canada
  3. Parkinson's Research Consortium
  4. Neuroscience Canada/Krembil Foundation
  5. Centre for Stroke Recovery
  6. World Class University program through the National Research Foundation of Korea
  7. Ministry of Education, Science and Technology, South Korea [R31-2008-000-20004-0]

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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 alpha-subunit of hypoxia-inducible factor-1 (HIF-1 alpha) by inhibiting HIF-VHL interaction. Consistent with this observation, DJ-1 deficiency leads to lowered HIF-1 alpha levels in models of both hypoxia and oxidative stress, two stresses known to stabilize HIF-1 alpha. We also demonstrate that HIF-1 alpha 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-1 alpha 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-1 alpha pathway.

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