Special Issue on "Cdk5 and Brain Disorders": Prologue.

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase primarily active in the nervous system.
• Cdk5 partners with regulatory subunits p35 and p39, influencing diverse cellular functions.
• Cdk5 regulates critical neuronal processes including development, migration, synaptic plasticity, and survival.

Purpose of the Study:

• To explore the dual role of Cdk5 in physiological functions and its deregulation in neurodegenerative diseases.
• To highlight the pathological significance of Cdk5 hyperactivation by the p25 cleavage product of p35.
• To identify Cdk5/p25 as a potential therapeutic target for neurodegenerative disorders.

Main Methods:

• Literature review and analysis of existing research on Cdk5 and its regulatory proteins.
• Examination of Cdk5's involvement in both normal neuronal function and pathological conditions.
• Focus on the mechanism of Cdk5 hyperactivation by p25 and its downstream effects.

Main Results:

• Cdk5, complexed with p35, is essential for normal nervous system function.
• Deregulation of Cdk5, specifically through hyperactivation by p25, leads to Tau and neurofilament hyperphosphorylation.
• This hyperphosphorylation is a key pathological event in neurodegenerative diseases such as Alzheimer's and ALS.

Conclusions:

• The Cdk5/p35 complex represents 'good Cdk5' essential for neuronal health.
• The Cdk5/p25 complex signifies 'bad Cdk5' implicated in neurodegeneration.
• Targeting the pathological Cdk5/p25 interaction offers a promising therapeutic strategy for neurodegenerative diseases.