Journal
PRION
Volume 6, Issue 4, Pages 364-370Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/pri.21250
Keywords
nitrosative stress; cyclin-dependent kinase 5; nitric oxide; neuronal NO synthase; transnitrosylation
Categories
Funding
- Alzheimer Association
- NIH [P01 HD29587, P01 ES016738, R01 EY09024, R01 EY05477, P30 NS057096]
- DoD [W81XWH-10-1-0093]
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Aberrant activation of Cdk5 has been implicated in the process of neurodegenerative diseases such as Alzheimer disease (AD). We recently reported that S-nitrosylation of Cdk5 (forming SNO-Cdk5) at specific cysteine residues results in excessive activation of Cdk5, contributing to mitochondrial dysfunction, synaptic damage and neuronal cell death in models of AD. Furthermore, SNO-Cdk5 acts as a nascent S-nitrosylase, transnitrosylating the mitochondrial fission protein Drp1 and enhancing excessive mitochondrial fission in dendritic spines. However, a molecular mechanism that leads to the formation of SNO-Cdk5 in neuronal cells remained obscure. Here, we demonstrate that neuronal nitric oxide synthase (NOS1) interacts with Cdk5 and that the close proximity of the two proteins facilitates the formation of SNO-Cdk5. Interestingly, as a negative feedback mechanism, Cdk5 phosphorylates and suppresses NOS1 activity. Thus, together with our previous report, these findings delineate an S-nitrosylation pathway wherein Cdk5/NOS1 interaction enhances SNO-Cdk5 formation, mediating mitochondrial dysfunction and synaptic loss during the etiology of AD.
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