Yan-Jie Guo1, Su-Yan Dong1, Xin-Xin Cui1, Ya Feng1, Te Liu2, Ming Yin3, Sheng-Han Kuo4, Eng-King Tan5, Wen-Juan Zhao3, Yun-Cheng Wu6. 1. Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China. 2. Shanghai Geriatric Institute of Chinese Medicine, Longhua Hospital, , Shanghai University of Traditional Chinese Medicine, Shanghai, P.R. China. 3. School of Pharmacy, Shanghai Jiao Tong University, Shanghai, P.R. China. 4. Department of Neurology, College of Physicians and Surgeons, Columbia University, NY, USA. 5. Department of Neurology, Singapore General Hospital, National Neuroscience Institute, Singapore. 6. Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China. yunchw@medmail.com.cn.
Abstract
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.
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.
Authors: Valérie Vingtdeux; Luca Giliberto; Haitian Zhao; Pallavi Chandakkar; Qingli Wu; James E Simon; Elsa M Janle; Jessica Lobo; Mario G Ferruzzi; Peter Davies; Philippe Marambaud Journal: J Biol Chem Date: 2010-01-14 Impact factor: 5.157
Authors: Konrad T Howitz; Kevin J Bitterman; Haim Y Cohen; Dudley W Lamming; Siva Lavu; Jason G Wood; Robert E Zipkin; Phuong Chung; Anne Kisielewski; Li-Li Zhang; Brandy Scherer; David A Sinclair Journal: Nature Date: 2003-08-24 Impact factor: 49.962