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

Mohammad Parsanejad, Yi Zhang, Dianbo Qu, Isabella Irrcher, Maxime W.C. Rousseaux, Hossein Aleyasin, Fatemeh Kamkar, Steve Callaghan, Ruth S. Slack, Tak W. Mak, Stephen Lee, Daniel Figeys, David S. Park

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)8043-8050
Number of pages8
JournalJournal of Neuroscience
Issue number23
StatePublished - 2014
Externally publishedYes


  • DJ-1
  • Oxidative stress
  • Parkinson's disease

ASJC Scopus subject areas

  • Neuroscience(all)


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