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 journalArticle

17 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)8043-8050
Number of pages8
JournalJournal of Neuroscience
Volume34
Issue number23
DOIs
StatePublished - 2014

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)

Fingerprint Dive into the research topics of 'Regulation of the VHL/HIF-1 pathway by DJ-1'. Together they form a unique fingerprint.

  • Cite this

    Parsanejad, M., Zhang, Y., Qu, D., Irrcher, I., Rousseaux, M. W. C., Aleyasin, H., Kamkar, F., Callaghan, S., Slack, R. S., Mak, T. W., Lee, S., Figeys, D., & Park, D. S. (2014). Regulation of the VHL/HIF-1 pathway by DJ-1. Journal of Neuroscience, 34(23), 8043-8050. https://doi.org/10.1523/JNEUROSCI.1244-13.2014