S-nitrosylation of Cdk5

Abstract

A berrant 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 SNOCdk5) 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. Cdk5 in Alzheimer Disease and Other Neurological DisordersCdk5 is a unique cyclin-dependent serine/threonine kinase that is activated by the two neuron-specific proteins p35 and p39.1-3 As a predominantly neuronalspecific kinase, Cdk5 is believed to lack a role in cell-cycle control but regulates an array of neuronal functions, including

Aberrant Protein S-Nitrosylation in Neurodegenerative Diseases

“…In the adult brain, Cdk5 is in close proximity to a membrane-bound protein complex containing nNOS/PSD-95/NMDAR. Cdk5 can form a complex with nNOS and become a target of S-nitrosylation under pathological conditions (Zhang et al, 2010; Qu et al, 2011; Qu et al, 2012). Indeed, SNO-Cdk5 is highly expressed in human AD postmortem brains but not in normal control brains (Qu et al, 2011).…”

Multiple faces of dynamin-related protein 1 and its role in Alzheimer's disease pathogenesis

“…According to their biotin-switch data, it has shown that SNO-Drp1 levels are elevated in Cdk5-transfected cells, which cause massive mitochondrial fragmentation compared with control plasmid-transfected cells. These findings suggest that transnitrosylation of NO from Cdk5 to Drp1 might be involved in the pathway to SNO-Cdk5–mediated spine loss, and eventually results in neuronal cell death AD [192, 193]. …”

Cdk5 activity in the brain – multiple paths of regulation

“…Thus, S-nitrosylated Cdk5 not only has higher kinase activity but also acts as a nascent transnitrosylase. Importantly, S-nitrosylation of Cdk5 is enhanced in the presence of Ab and N-methyl-D-aspartate (NMDA) (Qu et al, 2011;Qu et al, 2012), suggesting that deregulated Cdk5 also induces neurotoxicity through aberrant S-nitrosylation reactions under pathological conditions.…”