Cyclin-dependent kinase 5 (CDK5) (CDK5)

Cyclin-dependent kinase 5 (CDK5) is a proline-directed serine/threonine kinase predominantly expressed in post-mitotic neurons, where it regulates critical processes such as neuronal migration, neurite outgrowth, synaptogenesis, and neurotransmitter release. Unlike classical cyclin-dependent kinases, CDK5 is activated not by cyclins, but by neuron-specific regulatory proteins—primarily p35 and, to a lesser extent, p39. The CDK5/p35 complex is essential for proper brain development, including neuronal layering and axon guidance, and its aberrant regulation is implicated in a variety of disorders, particularly neurodegenerative diseases where hyperactive CDK5 leads to tau hyperphosphorylation and neurotoxicity. The kinase is a promising therapeutic target, but inhibition poses risks due to its essential physiological functions in the nervous system.

Other names

CDK5Cyclin-dependent kinase 5p35 (used to refer to its main neuron-specific activator, not the kinase itself)CDK5R1 (gene symbol for the activator p35, not the kinase)

Inhibition: Small molecules (such as roscovitine) inhibit CDK5 kinase activity, reducing aberrant phosphorylation events linked to disease. Modulation of activators: Drugs may prevent p35 binding/activation of CDK5, reducing activity in neuronal cells.