PT  - JOURNAL ARTICLE
AU  - Parsanejad, Mohammad
AU  - Zhang, Yi
AU  - Qu, Dianbo
AU  - Irrcher, Isabella
AU  - Rousseaux, Maxime W.C.
AU  - Aleyasin, Hossein
AU  - Kamkar, Fatemeh
AU  - Callaghan, Steve
AU  - Slack, Ruth S.
AU  - Mak, Tak W.
AU  - Lee, Stephen
AU  - Figeys, Daniel
AU  - Park, David S.
TI  - Regulation of the VHL/HIF-1 Pathway by DJ-1
AID  - 10.1523/JNEUROSCI.1244-13.2014
DP  - 2014 Jun 04
TA  - The Journal of Neuroscience
PG  - 8043--8050
VI  - 34
IP  - 23
4099  - http://www.jneurosci.org/content/34/23/8043.short
4100  - http://www.jneurosci.org/content/34/23/8043.full
SO  - J. Neurosci.2014 Jun 04; 34
AB  - 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.