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

TitleRegulation of the VHL/HIF-1 pathway by DJ-1
Authors
KeywordsDJ-1
Parkinson's disease
Oxidative stress
Issue Date2014
Citation
Journal of Neuroscience, 2014, v. 34, n. 23, p. 8043-8050 How to Cite?
AbstractDJ-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.
Persistent Identifierhttp://hdl.handle.net/10722/292826
ISSN
2023 Impact Factor: 4.4
2023 SCImago Journal Rankings: 2.321
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorParsanejad, Mohammad-
dc.contributor.authorZhang, Yi-
dc.contributor.authorQu, Dianbo-
dc.contributor.authorIrrcher, Isabella-
dc.contributor.authorRousseaux, Maxime W.C.-
dc.contributor.authorAleyasin, Hossein-
dc.contributor.authorKamkar, Fatemeh-
dc.contributor.authorCallaghan, Steve-
dc.contributor.authorSlack, Ruth S.-
dc.contributor.authorMak, Tak W.-
dc.contributor.authorLee, Stephen-
dc.contributor.authorFigeys, Daniel-
dc.contributor.authorPark, David S.-
dc.date.accessioned2020-11-17T14:57:18Z-
dc.date.available2020-11-17T14:57:18Z-
dc.date.issued2014-
dc.identifier.citationJournal of Neuroscience, 2014, v. 34, n. 23, p. 8043-8050-
dc.identifier.issn0270-6474-
dc.identifier.urihttp://hdl.handle.net/10722/292826-
dc.description.abstractDJ-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.-
dc.languageeng-
dc.relation.ispartofJournal of Neuroscience-
dc.subjectDJ-1-
dc.subjectParkinson's disease-
dc.subjectOxidative stress-
dc.titleRegulation of the VHL/HIF-1 pathway by DJ-1-
dc.typeArticle-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1523/JNEUROSCI.1244-13.2014-
dc.identifier.pmid24899725-
dc.identifier.pmcidPMC6608259-
dc.identifier.scopuseid_2-s2.0-84901781539-
dc.identifier.volume34-
dc.identifier.issue23-
dc.identifier.spage8043-
dc.identifier.epage8050-
dc.identifier.eissn1529-2401-
dc.identifier.isiWOS:000337630700030-
dc.identifier.issnl0270-6474-

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