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



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.



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.
Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
Yan-Jie
YJ
Guo
Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
Su-Yan
SY
Dong
Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
Xin-Xin
XX
Cui
Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
Ya
Y
Feng
Shanghai Geriatric Institute of Chinese Medicine, Longhua Hospital, , Shanghai University of Traditional Chinese Medicine, Shanghai, P.R. China.
Te
T
Liu
School of Pharmacy, Shanghai Jiao Tong University, Shanghai, P.R. China.
Ming
M
Yin
Department of Neurology, College of Physicians and Surgeons, Columbia University, NY, USA.
Sheng-Han
SH
Kuo
Department of Neurology, Singapore General Hospital, National Neuroscience Institute, Singapore.
Eng-King
EK
Tan
School of Pharmacy, Shanghai Jiao Tong University, Shanghai, P.R. China.
Wen-Juan
WJ
Zhao
Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China. yunchw@medmail.com.cn.
Yun-Cheng
YC
Wu
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000009:adverse effects; D000107:Acetylation / Q000187:drug effects; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology*; D051844:alpha-Synuclein / Q000378:metabolism*
C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D018696:Neuroprotective Agents; D013267:Stilbenes; D051844:alpha-Synuclein; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D000077185:Resveratrol; D004298:Dopamine
LC3 deacetylation; Parkinson's disease; Resveratrol; SIRT1; α-synuclein