Resveratrol alleviates MPTP-induced motor impairments and pathological changes by autophagic degradation of α-synuclein via SIRT1-deacetylated LC3

• Published in: Molecular nutrition & food research 2016-10, Vol.60 (10), p.2161-2175
• Main Authors: Guo, Yan-Jie, Dong, Su-Yan, Cui, Xin-Xin, Feng, Ya, Liu, Te, Yin, Ming, Kuo, Sheng-Han, Tan, Eng-King, Zhao, Wen-Juan, Wu, Yun-Cheng
• Format: Article
• Language: English
• Subjects: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine - adverse effects; Acetylation - drug effects; alpha-Synuclein - metabolism; animal models; Animals; Autophagy - drug effects; Behavior, Animal - drug effects; Corpus Striatum - drug effects; Corpus Striatum - metabolism; cytoplasm; Disease Models, Animal; dopamine; Dopamine - metabolism; grapes; LC3 deacetylation; Male; mice; Mice, Inbred C57BL; Microtubule-Associated Proteins - metabolism; neurons; Neuroprotective Agents - pharmacology; neuroprotective effect; Parkinson disease; Parkinson Disease, Secondary - chemically induced; Parkinson Disease, Secondary - drug therapy; Parkinson Disease, Secondary - metabolism; Parkinson's disease; red wines; Resveratrol; SIRT1; Sirtuin 1 - metabolism; Stilbenes - pharmacology; tyrosine 3-monooxygenase; Vitaceae; α-synuclein
• ISSN: 1613-4125; 1613-4133
• DOI: 10.1002/mnfr.201600111

Scope The accumulation of misfolded α‐synuclein in dopaminergic neurons is the leading cause of Parkinson's disease (PD). Resveratrol (RV), a polyphenolic compound derived from grapes and red wine, exerts a wide range of beneficial effects via activation of sirtuin 1 (SIRT1) and induction of vitagenes. Here, we assessed the role of RV in a 1‐methyl‐4‐phenyl‐1, 2, 3, 6‐tetrahydropyridine (MPTP) induced mouse model of PD and explored its potential mechanisms. Methods and results RV and EX527, a specific inhibitor of SIRT1, were administered before and after MPTP treatment. RV protected against MPTP‐induced loss of dopaminergic neurons, and decreases in tyrosine hydroxylase and dopamine levels, as well as behavioral impairments. Meanwhile, RV administration activated SIRT1. Microtubule‐associated protein 1 light chain 3 (LC3) was then deacetylated and redistributed from the nucleus to the cytoplasm, which provoked the autophagic degradation of α‐synuclein in dopaminergic neurons. Furthermore, EX527 antagonized the neuroprotective effects of RV by reducing LC3 deacetylation and subsequent autophagic degradation of α‐synuclein. Conclusion We showed that RV ameliorated both motor deficits and pathological changes in MPTP‐treated mice via activation of SIRT1 and subsequent LC3 deacetylation‐mediated autophagic degradation of α‐synuclein. Our observations suggest that RV may be a potential prophylactic and/or therapeutic agent for PD. In dopaminergic neurons, resveratrol (RV) directly or indirectly activates sirtuin1 (SIRT1; while EX527 inhibits SIRT1), LC3 is then deacetylated by SIRT1 and redistributed from the nucleus to the cytoplasm, which provokes the autophagic degradation of α‐synuclein, thus preventing the neuron loss in substantia nigra, attenuating pathological changes and behavior impairments.We think these findings propose a mechanism to support RV as a prophylactic or therapeutic agent for Parkinson's disease.