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

Anuri Shah, Jianfei Chao, Cristina Legido-Quigley, Raymond Chuen-Chung Chang

13 Citations (Scopus)

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.

Original languageEnglish
JournalNutritional Neuroscience
Volume24
Issue number3
Pages (from-to)181-196
Number of pages16
ISSN1028-415X
DOIs
Publication statusPublished - 2021

Keywords

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

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