Parkinson's disease (PD) is the most common neurodegenerative motor disorder, whose
clinical features are rest tremor, bradykinesia, muscular rigidity and postural instability.
Although most reported cases are sporadic, a handful of familial cases and their causative
genes have been identified. Loss-of-function mutations in DJ-1, one of these genes, are
responsible for 1% of familial PD cases. Our laboratory has previously reported that DJ-1-
lacking neurons are sensitive to oxidative stress, induced by hydrogen peroxide or the
neurotoxin MPTP. To investigate the possible mechanisms through which DJ-1 protects
against oxidative stress, we performed a proteomic screen and identified Von Hippel Lindau (VHL) and Paraoxonase2 (PON2) as potential DJ-1 interacting partners. VHL is an E3 ubiquitin ligase which, in normal conditions, poly-ubiquitinates HIF-1 , a subunit of a master hypoxic/oxidative stress transcription factor, whose function is protective in oxidative and hypoxic stresses. In the present study, we provided further evidence of interaction of DJ-1 with VHL. We also demonstrated that HIF-1 protein level, as an indicator of VHL activity, is lower in cells lacking DJ-1, suggesting the inhibitory role of DJ-1 on VHL. Our in vitro studies also showed that DJ-1 inhibits ubiquitin ligase activity of VHL on HIF-1 by reducing the VHL-HIF-1 interaction. Importantly, accumulation of
HIF-1 protects embryonic cortical neurons against MPP+ induced neuronal death. Finally,
we confirmed the impairment of HIF-1 response to oxidative stress in human
lymphoblastoids of DJ-1-linked PD cases. In the second part of this study, we demonstrated
the interaction of DJ-1 and PON2. Interestingly, PON2 lactonase activity is reduced in DJ-1 deficient cells which could be rescued by re-introduction of DJ-1, suggesting a modulating role of DJ-1 on PON2 activity. In addition, PON2 deficiency, like DJ-1 deficiency, hypersensitizes
neurons to MPP+, which could be rescued by over-expression of PON2 in both
cases. Taken together, our data provide evidence that DJ-1 exerts its protective role by inhibiting VHL activity, enhancing HIF-1 stability, and increasing PON2 pro-survival
function in PD models.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OOU.#10393/24049 |
| Date | 23 April 2013 |
| Creators | Parsanejad, Mohammad |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Thèse / Thesis |
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