The effect of oxyresveratrol on endoplasmic reticulum stress in Parkinson's disease

Abstract

Parkinson’s disease (PD) results from a loss of dopaminergic neurons and the presence of intracytoplasmic inclusions known as Lewy bodies (LB), culminating in a loss of motor function. While the risk factors are multifactorial in nature, there is no breakthrough curative therapy for PD. Oxyresveratrol (OXY) is a potent antioxidant found in Mulberry fruits. We have previously reported the neuroprotective potential of OXY in an in vitro parkinsonian model. The aim of this study is to investigate the effects of OXY on specific pathways implicated in PD. Human neuroblastoma SH-SY5Y cells were stably transfected to express the A30P familial mutant of alpha synuclein (αS), which is the main constituent of LBs. Forty eight hours after treatment with OXY, we observed a reduction in the misfolded, oligomeric species of αS. A build-up of misfolded protein leads to stress in the endoplasmic reticulum (ER), subsequently activating the unfolded protein response (UPR). Therefore, our next aim was to study the effects of OXY on this pathological pathway in a PD model. SH-SY5Y cells were treated with 6-hydroxydopamine, a parkinsonian mimetic toxin, after pre-treatment with OXY. Activation of signaling molecules involved in the UPR were then assessed. The results showed that OXY does indeed modulate the UPR, in turn mitigating ER stress. This gives us an idea of the underlying mechanism by which OXY exerts neuroprotective effects in PD. The study is supported by Health and Medical Research Fund 02131496.