Summary of role of Cdk5 in physiology and pathology. Cdk5 is a proline-directed serine/threonine kinase and gets activated by its neuron specific promoter p35. Under normal physiological (normal) conditions, Cdk5/p35 is involved with various roles in neuronal development, cognition and memory, cell adhesion, phosphorylation of cytoskeletal proteins, and synaptic plasticity. When the neurons are stressed due to various insults like oxidative stress, inflammation, mitochondrial dysfunction, or toxicity due to Aβ or glutamate, there is an increase in Ca2+ leading to activation of calpain, a protease. Calpain cleaves p35 to p25 deregulating Cdk5 activity as p25 forms a hyperactive and more stable complex with Cdk5. Cdk5/p25 activity causes aberrant phosphorylation of various proteins leading to conformational changes inducing gain of toxic function. Misfolded proteins lead to self-aggregation thereby overwhelming the system by blocking transport and disrupting synaptic activity. This ultimately leads to degeneration of neurons and finally be the cause of various neurodegenerative diseases like AD, ALS, PD, and HD.
