title: S-nitrosylation of Cdk5: potential implications in amyloid-β-related neurotoxicity in Alzheimer disease.
abstract: Aberrant activation of Cdk5 has been implicated in the process of neurodegenerative diseases such as Alzheimer's 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.
authors.affiliation: Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Qu
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nakamura
authors.forename: Emily A
authors.initials: EA
authors.lastname: Holland
authors.forename: Scott R
authors.initials: SR
authors.lastname: McKercher
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Lipton
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D000682:Amyloid / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D004789:Enzyme Activation; D057809:HEK293 Cells; D006801:Humans; D009474:Neurons / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D009603:Nitroso Compounds / Q000378:metabolism*; D051381:Rats
chemical_list: D000682:Amyloid; D009603:Nitroso Compounds; D052248:Nitric Oxide Synthase Type I; D051360:Cyclin-Dependent Kinase 5