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

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.

 

Comments:

It sounds like you're discussing a study involving the role of S-nitrosoglutathione reductase (GSNOR) in Parkinson's disease (PD) using a mouse model induced by MPTP. The study suggests that GSNOR plays a significant role in regulating protein S-nitrosation and impacts PD pathology via its involvement in CDK5-mediated autophagy triggered by MPTP.

The findings imply that increased GSNOR expression correlates with MPTP-induced CDK5 activation, leading to autophagy, behavioral dyskinesias, and the loss of dopaminergic neurons. However, when GSNOR was knocked out or inhibited with N6022, it alleviated the PD-like symptoms and neurotoxicity caused by MPTP. The mechanism here seems to involve GSNOR affecting CDK5 S-nitrosation at Cys83, thereby modulating CDK5 kinase activity and subsequent autophagy.

Understanding the interplay between GSNOR, CDK5, and autophagy sheds light on potential therapeutic targets for Parkinson's disease. This research might pave the way for interventions aiming to modulate GSNOR or CDK5 activity to mitigate PD pathology.

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Cat.No.	Product Name	Information
S7589	N6022	N6022 is a selective, and reversible inhibitor of S-nitrosoglutathione reductase (GSNOR) with IC50 of 8 nM and Ki of 2.5 nM. Phase 1/2.

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