Cdk5-Mediated Mechanisms in Neurodegenerative Diseases

Cdk5 is a unique cyclin-dependent kinase activated by neuron-specific co-factors that orchestrates synaptic development, axonal transport and neuronal survival. Under physiological conditions, Cdk5 associates with p35 to regulate cytoskeletal dynamics, neurotransmitter release and memory formation. In neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and frontotemporal dementia, aberrant cleavage of p35 to longer-lived p25 by calpain leads to sustained Cdk5 hyperactivity. This shift perturbs tau phosphorylation, microtubule stability and axonal trafficking, and it fuels neuroinflammatory cascades through glial activation. Converging evidence implicates dysregulated Cdk5 signalling in synaptic loss, mitochondrial dysfunction and neuronal apoptosis, establishing this pathway as both a driver of pathology and a promising therapeutic target. Advances in selective Cdk5 inhibition and modulation of its activators hold potential for disease-modifying interventions across a spectrum of neurodegenerative conditions.

Research from Nature Portfolio

No recent Nature Portfolio content available.

Cdk5-Mediated Mechanisms in Neurodegenerative Diseases publication trend

The graph below shows the total number of articles in cdk5-mediated mechanisms in neurodegenerative diseases across all publications each year (not limited to Nature Index journals).

Technical terms

Cdk5: A serine/threonine kinase in post-mitotic neurons, activated by p35 or p25, that regulates cytoskeletal dynamics, synaptic transmission and cell survival.

p35/p25: Neuron-specific activator of Cdk5; p25 is a calpain-cleaved, longer-lived fragment that drives pathological Cdk5 hyperactivity.

Tau hyperphosphorylation: Excessive phosphorylation of tau protein at Ser/Thr-Pro sites, leading to microtubule destabilisation and neurofibrillary tangle formation.

Neuroinflammation: Innate immune response in the central nervous system, characterised by glial activation and release of pro-inflammatory cytokines.

Axonal transport: Movement of organelles and proteins along microtubules within axons, essential for synaptic health and neuronal viability.

References

1. The lemur tail kinase family in neuronal function and disfunction in neurodegenerative diseases. Cellular and Molecular Life Sciences (2024).
2. Inhibition of cyclin-dependent kinase 5 affects early neuroinflammatory signalling in murine model of amyloid beta toxicity. Journal of Neuroinflammation (2018).
3. Calpain-dependent Proteolytic Cleavage of the p35 Cyclin-dependent Kinase 5 Activator to p25*. Journal of Biological Chemistry (2000).
4. Truncation of CDK5 Activator p35 Induces Intensive Phosphorylation of Ser202/Thr205 of Human Tau*. Journal of Biological Chemistry (2002).