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Autophagy. 2015;11(10):1745-59. doi: 10.1080/15548627.2015.1082020.

Melatonin attenuates MPTP-induced neurotoxicity via preventing CDK5-mediated autophagy and SNCA/α-synuclein aggregation.

Su LY1,2, Li H1,2, Lv L1,2, Feng YM1, Li GD1,2,3, Luo R1, Zhou HJ1, Lei XG1, Ma L1,2, Li JL1,4, Xu L1,5, Hu XT1,4,5, Yao YG1,2,4,5.

Author information

1
a Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences; Kunming Institute of Zoology ; Kunming, Yunnan , China.
2
b Kunming College of Life Science; University of Chinese Academy of Sciences ; Kunming, Yunnan , China.
3
d School of Life Science; Anhui University ; Hefei, Anhui , China.
4
c Kunming Primate Research Center of the Chinese Academy of Sciences; Kunming Institute of Zoology; Chinese Academy of Sciences ; Kunming, Yunnan , China.
5
e CAS Center for Excellence in Brain Science and Intelligence Technology; Chinese Academy of Sciences ; Shanghai , China.

Abstract

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.

KEYWORDS:

CDK5; MPTP; SNCA; TH; autophagy; melatonin

PMID:
26292069
PMCID:
PMC4824603
DOI:
10.1080/15548627.2015.1082020
[Indexed for MEDLINE]
Free PMC Article

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