Abstract
Although a loss-of-function mutation has been identified in familial Parkinson’s disease PARK7, the wild-type of DJ-1 is known to act as an oxidative stress sensor in neuronal cells. Recently, we identified UCP0045037 as a compound that bound to the reduced form of DJ-1 by in silico virtual screening. In this study, we determined the neuroprotective effects of UCP0045037 against focal cerebral ischemia-induced neurodegeneration in rats. Hydrogen peroxide-induced cell death was significantly inhibited by UCP0045037 in both rat mesencephalic dopaminergic neurons and human normal SH-SY5Y cells. In contrast, DJ-1-knockdown SH-SY5Y cells lost the protective activity of UCP0045037. These results suggest that UCP0045037 interacts with endogenous DJ-1 and produces a neuroprotective response.
Highlights
DJ-1 was first discovered as a novel oncogene product in collaboration with activated small GTPbinding protein ras [1], and was later identified as a causative gene in the seventh type of familialParkinson’s disease, PARK7 [2]
We previously found that neuronal death induced by occlusion of the middle cerebral artery (MCA)
To clarify the effect of the DJ-1 ligand UCP0045037, which can bind to the pocket region at the reduced Cys106 of DJ-1 protein [16], in the in vivo ischemic brain, we performed an intrastriatal microinjection of this DJ-1 ligand and subjected to the animals to 90 min of MCA occlusion (MCAO) and reperfusion (Figure 2)
Summary
DJ-1 was first discovered as a novel oncogene product in collaboration with activated small GTPbinding protein ras [1], and was later identified as a causative gene in the seventh type of familial. Among the DJ-1 ligands identified in silico, UCP0045037 (Figure 1) had the highest binding constant (docking score) toward the pocket of the reduced Cys106 region and exhibited neuroprotective effects in a Parkinson’s disease model in rats, which were microinjected with 6-hydroxydopamine into the substantia nigra [16]. It is not yet known whether UCP0045037 is effective in brain stroke. To clarify the effects of UCP0045037 and DJ-1 on brain stroke and oxidative insult, we examined the effects of UCP0045037 on focal ischemia/reperfusion-induced oxidative brain damage in an in vivo neuronal model and on hydrogen peroxide (H2O2)-induced cell death in rat ventral mesencephalic neurons; or in normal and DJ-1-knockdown SH-SY5Y cells in an in vitro cultured neuronal model
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