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Autophagy is involved in the pathogenesis of neurodegenerative diseases including Parkinsons 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 Cyclin-dependent kinase 5(CDK5).MPTP treatment significantly reduced the neuronal neuritesof the cultured primary neurons.These effects of MPTP could be counteracted by melatonin.Consistent with these observations on cell line and primary neurons,decreased tyrosine hydroxylase(TH)-positive cells and dendrites of dopaminergic neurons were also found in the substantia nigra pars compacta(SNc).A decreased TH expression was accompanied with an up-regulation of CDK5 and enhanced autophagic activity in the striatum of mice with MPTP injection.These changes could be salvaged by melatonin.Importantly,melatonin reduced MPTP-induced α-synuclein aggregation which is widely believed to trigger the pathogenesis of PD.Finally,melatonin also counteracted the Parkinsons behavior in mice injected with MPTP.Our findings uncover a potent role of autophagy in the pathogenesis of PD,and suggest that control of autophagic pathways may provide an important clue for exploring potential targets for novel therapeutics ofPD.