RT Journal Article
SR Electronic
T1 Regulation of the VHL/HIF-1 Pathway by DJ-1
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 8043
OP 8050
DO 10.1523/JNEUROSCI.1244-13.2014
VO 34
IS 23
A1 Parsanejad, Mohammad
A1 Zhang, Yi
A1 Qu, Dianbo
A1 Irrcher, Isabella
A1 Rousseaux, Maxime W.C.
A1 Aleyasin, Hossein
A1 Kamkar, Fatemeh
A1 Callaghan, Steve
A1 Slack, Ruth S.
A1 Mak, Tak W.
A1 Lee, Stephen
A1 Figeys, Daniel
A1 Park, David S.
YR 2014
UL http://www.jneurosci.org/content/34/23/8043.abstract
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.