Oxyresveratrol exerts ATF4-and Grp78-mediated neuroprotection against endoplasmic reticulum stress in experimental Parkinson's disease

Objectives Endoplasmic reticulum (ER) stress is one of the key mechanisms contributing to Parkinson's disease (PD) pathology. Pathways triggered by ER stress are protective at early stages and initiate apoptosis when the damage is extensive. Methods We have previously reported that oxyresveratrol rescues cells from oxidative stress and apoptosis in a cell culture model of PD. The aim of this study was to investigate whether the neuroprotective mechanism of oxyresveratrol extends to PD-associated ER stress. For this purpose, we employed two cellular models; to induce severe ER stress, Mes23.5 cells were treated with 6-hydroxydopamine (6-OHDA) and for ER stress driven by chaperones, human neuroblastoma cells were stably transfected to overexpress familial mutants of alpha-synuclein (alpha-syn). Results Our results indicate that oxyresveratrol exhibits distinct modes of protection in both models. In the 6-OHDA model, it inhibited the transcription of activating transcription factor 4 (ATF4), which controls the fate of pro-apoptotic proteins. On the other hand, in the alpha-syn model, oxyresveratrol suppressed mutant A30P oligomer formation, thereby facilitating a reduction of the ER-chaperone, 78-kDa glucose-regulated protein (Grp78). Discussion In summary, oxyresveratrol is protective against ER stress induced by two different triggers of PD. Owing to its wide range of defense mechanisms, oxyresveratrol is an ideal candidate for a multifactorial disease like PD.

Automated summary

The study demonstrates that oxyresveratrol has protective effects against ER stress in two different PD cell models, acting through diverse mechanisms and presenting as a promising candidate for PD treatment.