The S-nitrosoglutathione reductase (GSNOR) is a key denitrosating enzyme that regulates protein S-nitrosation, a process which has been found to be involved in the pathogenesis of Parkinson's disease (PD). However, the physiological function of GSNOR in PD remains unknown. In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model, we found that GSNOR expression was significantly increased and accompanied by autophagy mediated by MPTP-induced cyclin dependent kinase 5 (CDK5), behavioral dyskinesias and dopaminergic neuron loss. Whereas, knockout of GSNOR, or treatment with the GSNOR inhibitor N6022, alleviated MPTP-induced PD-like pathology and neurotoxicity. Mechanistically, deficiency of GSNOR inhibited MPTP-induced CDK5 kinase activity and CDK5-mediated autophagy by increasing S-nitrosation of CDK5 at Cys83. Our study indicated that GSNOR is a key regulator of CDK5 S-nitrosation and is actively involved in CDK5-mediated autophagy induced by MPTP.
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