Cyclin-dependent kinase 5

Cyclin-dependent kinase 5 (CDK5) is a proline-directed serine/threonine kinase essential for neuronal cell cycle arrest and differentiation (UniProt: Q00535). It phosphorylates numerous substrates including tau (MAPT), MAP proteins, synaptic proteins, and regulators of cell survival and apoptosis. CDK5 is activated by interaction with regulatory subunits p35 and p39, particularly in postmitotic neurons, and regulates critical processes including neuronal migration, axonal growth, synaptogenesis, and neurotransmission. The kinase also participates in DNA damage response and circadian clock regulation via CLOCK protein phosphorylation.

CDK5 functions broadly across the central nervous system in neuronal development and synaptic plasticity. UniProt disease annotations include lissencephaly 7 with cerebellar hypoplasia, a severe cortical development disorder (UniProt: Q00535). The protein's extensive phosphorylation of cytoskeletal and synaptic proteins positions it as a key regulator of neuronal morphology and function.

In Alzheimer's disease, CDK5 is significantly down-regulated in post-mortem AD brain tissue compared to age-matched controls (mean log2FC: −0.42; Chaparral AD proteomics). This down-regulation was observed in human post-mortem brain samples analyzed by TMT-labeled proteomics across subcellular fractions, suggesting potential impairment of CDK5-dependent neuronal processes in AD pathology.