GSNOR deficiency attenuates MPTP-induced neurotoxicity and autophagy by facilitating CDK5 S-nitrosation in a mouse model of Parkinson's disease

Free Radic Biol Med. 2022 Aug 20;189:111-121. doi: 10.1016/j.freeradbiomed.2022.07.016. Epub 2022 Jul 30.

Abstract

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.

Keywords: Autophagy; CDK5; GSNOR; Parkinson's disease; S-nitrosation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Alcohol Dehydrogenase / metabolism*
  • Animals
  • Autophagy
  • Cyclin-Dependent Kinase 5 / genetics
  • Cyclin-Dependent Kinase 5 / metabolism
  • Disease Models, Animal
  • Dopaminergic Neurons / metabolism
  • MPTP Poisoning* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Nitrosation
  • Parkinson Disease* / drug therapy
  • Parkinson Disease* / genetics
  • Parkinson Disease* / metabolism

Substances

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Adh5 protein, mouse
  • Alcohol Dehydrogenase
  • Cyclin-Dependent Kinase 5