Anuri Shah1,2, Jianfei Chao1, Cristina Legido-Quigley2,3, Raymond Chuen-Chung Chang1,4. 1. Laboratory of Neurodegenerative Diseases, School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong S.A.R, People's Republic of China. 2. Institute of Pharmaceutical Science, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom. 3. Steno Diabetes Center Copenhagen, Gentofte, Denmark. 4. State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong S.A.R, People's Republic of China.
Abstract
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 α-synuclein (α-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 α-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.
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 α-synuclein (α-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 α-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.
Entities:
Keywords:
6-OHDA; ER stress oxyresveratrol; Parkinson’s disease; α-synuclein