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

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.

KEYWORDS:

• α-synuclein
• ER stress oxyresveratrol
• Parkinson’s disease
• 6-OHDA

Acknowledgments

We thank Dr. Mingfu Wang for kindly providing the oxyresveratrol used in this study and Dr. Atsushi Takeda for providing the constructs of α-synuclein. This study was supported by the Health Medical Research Fund (02131496) from the Food and Health Bureau of Hong Kong S.A.R Government to RCCC. AS is funded by the Postgraduate Scholarship from The University of Hong Kong.

Disclosure statement

No potential conflict of interest was reported by the authors.

Notes on contributors

Dr. Anuri Shah obtained an undergraduate degree in Pharmacy and a Master’s degree in Molecular Pharmacology and Toxicology at the University of Southern California. She recently received a Joint PhD in Neuropharmacology from The University of Hong Kong and King’s College London. Her doctoral research was on the neuroprotective effects of oxyresveratrol on experimental models of Parkinson’s disease using a biochemical and metabolomics approach.

Dr. Jianfei Chao received her undergraduate education in Chinese Medicine Pharmacology. She then obtained a Master’s degree in Phytochemistry at China Pharmaceutical University followed by a PhD from the School of Biological Sciences, The University of Hong Kong. Her thesis work is on the neuroprotective effects of oxyresveratrol. She is currently working as a postdoctoral fellow/scientist in the Beckman Research Institute.

Dr. Cristina Legido-Quigley leads the metabolomics and bioinformatics laboratory at Steno Diabetes Centre, Copenhagen. She is also an Associate Professor at King’s College London and a visiting faculty at Guizhou Medical University. Dr. Legido-Quigley’s main research focus is to find “biomarker molecules” that are related to a disease, which can be used for diagnosis and treatment. Her laboratory's findings are molecules that are related with memory in dementia and ageing, with liver quality before liver transplantation, with metabolism enhancement in athletes and with inflammation due to toxicity.

Dr. Raymond Chuen-Chung Chang is the Lab Chief for the Laboratory of Neurodegenerative Diseases in the School of Biomedical Sciences, LKS Faculty of Medicine, member in The State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong. Dr. Chang is the organizer and Secretary of HKU Alzheimer’s Disease Research Network and has been organizing the International Alzheimer’s Disease Conference in Hong Kong every year since 2000. Dr. Chang’s research interest is on four directions. (1) Pathophysiological changes of Alzheimer’s disease (AD), (2) how different risk factors (post-operative cognitive dysfunctions, periodontitis, depression, cigarette smoking, air pollutants) stimulate systemic inflammation to affect neuroimmune responses leading to AD, (3) spreading of neurodegeneration in Parkinson’s disease dementia, and (4) neurodegeneration of the retina and deterioration of visual functions in Alzheimer’s disease. He has published over 147 peer-reviewed papers, 15 book chapters and edited 4 books in these areas. Dr. Chang is the Chief Editor for “American Journal of Alzheimer’s Disease and Other Dementias”, a Senior Editor for “Journal of Neuroimmune Pharmacology”, an Associate handling Editor for “Frontiers in Neurology”, “Frontiers in Neurosciences” and “Frontiers in Psychiatry”.

Additional information

Funding

This study was supported by the Health Medical Research Fund (02131496) from the Food and Health Bureau of Hong Kong S.A.R Government.