Melatonin attenuates MPTP-induced neurotoxicity via preventing CDK5-mediated autophagy and SNCA/α-synuclein aggregation.
Autophagy is involved in the pathogenesis of neurodegenerative diseases including Parkinson disease (PD). However, little is known about the regulation of autophagy in neurodegenerative process. In this study, we characterized aberrant activation of autophagy induced by neurotoxin 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) and demonstrated that melatonin has a protective effect on neurotoxicity. We found an excessive activation of autophagy in monkey brain tissues and C6 cells, induced by MPTP, which is mediated by CDK5 (cyclin-dependent kinase 5). MPTP treatment significantly reduced total dendritic length and dendritic complexity of cultured primary cortical neurons and melatonin could reverse this effect. Decreased TH (tyrosine hydroxylase)-positive cells and dendrites of dopaminergic neurons in the substantia nigra pars compacta (SNc) were observed in MPTP-treated monkeys and mice. Along with decreased TH protein level, we observed an upregulation of CDK5 and enhanced autophagic activity in the striatum of mice with MPTP injection. These changes could be salvaged by melatonin treatment or knockdown of CDK5. Importantly, melatonin or knockdown of CDK5 reduced MPTP-induced SNCA/α-synuclein aggregation in mice, which is widely thought to trigger the pathogenesis of PD. Finally, melatonin or knockdown of CDK5 counteracted the PD phenotype in mice induced by MPTP. Our findings uncover a potent role of CDK5-mediated autophagy in the pathogenesis of PD, and suggest that control of autophagic pathways may provide an important clue for exploring potential target for novel therapeutics of PD.
a Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences; Kunming Institute of Zoology ; Kunming, Yunnan , China.|b Kunming College of Life Science; University of Chinese Academy of Sciences ; Kunming, Yunnan , China.
Ling-Yan
LY
Su
a Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences; Kunming Institute of Zoology ; Kunming, Yunnan , China.|b Kunming College of Life Science; University of Chinese Academy of Sciences ; Kunming, Yunnan , China.
Hao
H
Li
a Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences; Kunming Institute of Zoology ; Kunming, Yunnan , China.|b Kunming College of Life Science; University of Chinese Academy of Sciences ; Kunming, Yunnan , China.
Li
L
Lv
a Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences; Kunming Institute of Zoology ; Kunming, Yunnan , China.
Yue-Mei
YM
Feng
a Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences; Kunming Institute of Zoology ; Kunming, Yunnan , China.|b Kunming College of Life Science; University of Chinese Academy of Sciences ; Kunming, Yunnan , China.|d School of Life Science; Anhui University ; Hefei, Anhui , China.
Guo-Dong
GD
Li
a Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences; Kunming Institute of Zoology ; Kunming, Yunnan , China.
Rongcan
R
Luo
a Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences; Kunming Institute of Zoology ; Kunming, Yunnan , China.
He-Jiang
HJ
Zhou
a Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences; Kunming Institute of Zoology ; Kunming, Yunnan , China.
Xiao-Guang
XG
Lei
a Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences; Kunming Institute of Zoology ; Kunming, Yunnan , China.|b Kunming College of Life Science; University of Chinese Academy of Sciences ; Kunming, Yunnan , China.
Liang
L
Ma
a Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences; Kunming Institute of Zoology ; Kunming, Yunnan , China.|c Kunming Primate Research Center of the Chinese Academy of Sciences; Kunming Institute of Zoology; Chinese Academy of Sciences ; Kunming, Yunnan , China.
Jia-Li
JL
Li
a Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences; Kunming Institute of Zoology ; Kunming, Yunnan , China.|e CAS Center for Excellence in Brain Science and Intelligence Technology; Chinese Academy of Sciences ; Shanghai , China.
Lin
L
Xu
a Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences; Kunming Institute of Zoology ; Kunming, Yunnan , China.|c Kunming Primate Research Center of the Chinese Academy of Sciences; Kunming Institute of Zoology; Chinese Academy of Sciences ; Kunming, Yunnan , China.|e CAS Center for Excellence in Brain Science and Intelligence Technology; Chinese Academy of Sciences ; Shanghai , China.
Xin-Tian
XT
Hu
a Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences; Kunming Institute of Zoology ; Kunming, Yunnan , China.|b Kunming College of Life Science; University of Chinese Academy of Sciences ; Kunming, Yunnan , China.|c Kunming Primate Research Center of the Chinese Academy of Sciences; Kunming Institute of Zoology; Chinese Academy of Sciences ; Kunming, Yunnan , China.|e CAS Center for Excellence in Brain Science and Intelligence Technology; Chinese Academy of Sciences ; Shanghai , China.
Yong-Gang
YG
Yao
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000818:Animals; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism; D000882:Haplorhini; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D009498:Neurotoxins / Q000494:pharmacology; D010300:Parkinson Disease / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism*
D009498:Neurotoxins; D051844:alpha-Synuclein; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D051360:Cyclin-Dependent Kinase 5; D008550:Melatonin; D004298:Dopamine
CDK5; MPTP; SNCA; TH; autophagy; melatonin