Cyclin-dependent kinase 5

Cdk5 functions

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Cyclin-dependent kinase 5 (CDK5) is a protein that in humans is encoded by the CDK5 gene. CDK5 belongs to the cyclin-dependent kinase family, a group of serine/threonine kinases that are involved in the regulation of the cell cycle. Unlike other members of this family, CDK5 does not play a role in controlling the cell cycle. Instead, it is involved in various neuronal processes, including neuron development, neuronal migration, and neuronal survival. CDK5 is also implicated in the regulation of synaptic function and plasticity, making it crucial for learning and memory.

Function

CDK5 is unique among CDKs due to its predominant expression in post-mitotic neurons. It is activated by binding to its activators, p35 and p39, rather than cyclins. Once activated, CDK5 phosphorylates a variety of substrates involved in the nervous system's development and function. These substrates include neurofilaments, tau, and dendritic spines, which are essential for neuronal morphology and signal transduction.

Regulation

The activity of CDK5 is tightly regulated through its association with its activators, p35 and p39, which are themselves regulated by proteolysis and phosphorylation. The conversion of p35 to its truncated form, p25, by calpain results in prolonged activation of CDK5, leading to hyperphosphorylation of substrates. This dysregulation of CDK5 activity is associated with several neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease.

Pathology

Aberrant CDK5 activity due to the overexpression of p25 has been implicated in the pathogenesis of neurodegenerative diseases. Hyperphosphorylation of tau by CDK5 results in the formation of neurofibrillary tangles, a hallmark of Alzheimer's disease. In addition, CDK5 is involved in the phosphorylation of other proteins that contribute to the neurodegenerative process, including amyloid precursor protein (APP) and alpha-synuclein, linking it to a broader spectrum of neurological disorders.

Research and Clinical Implications

Given its role in neurodegeneration, CDK5 has become a target for therapeutic intervention. Inhibitors of CDK5 are being explored as potential treatments for neurodegenerative diseases. However, the challenge lies in developing inhibitors that can selectively target the pathological activities of CDK5 without affecting its normal physiological functions.

See Also

• Cyclin-dependent kinase
• Neurodegeneration
• Alzheimer's disease
• Parkinson's disease
• Tau protein