CDK5 activator protein p25 preferentially binds and activates GSK3β

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Glycogen synthase kinase 3β (GSK3β) and cyclin-dependent kinase 5 (CDK5) are implicated in Alzheimer's disease pathogenesis.
• Both kinases share similar 3D structures, suggesting potential overlap in cofactor binding.
• CDK5 is typically activated by p35/p39, while GSK3β's interactions with these activators are less understood.

Purpose of the Study:

• To investigate the interaction between GSK3β and cyclin-like proteins, specifically p35 and its cleavage product p25.
• To determine if GSK3β can bind to p25 and if this interaction affects its substrate specificity and role in neurodegeneration.
• To elucidate the role of GSK3β:p25 complex in neuronal dysfunction and compare it to CDK5:p25 interactions.

Main Methods:

• Investigated protein-protein interactions using co-expression and FRET analysis in cellular models.
• Utilized in silico modeling to predict binding sites and functional consequences.
• Assessed neurodegeneration phenotypes and employed siRNA to evaluate the roles of GSK3β and CDK5.

Main Results:

• GSK3β unexpectedly binds to p25, a cleavage product of p35, and outcompetes CDK5 for p25 binding.
• The GSK3β:p25 interaction enhances tau phosphorylation and decreases β-catenin phosphorylation, linked to inhibition of the GSK3β/AXIN/APC complex.
• Co-expression of GSK3β and p25 induces a more severe neurodegeneration phenotype than CDK5 and p25; siRNA against GSK3β is more effective in blocking p25-induced neuronal damage.

Conclusions:

• The p25-mediated neurodegenerative effects, often attributed to CDK5, may be significantly mediated by GSK3β.
• GSK3β's interaction with p25 alters its kinase activity and substrate specificity, contributing to Alzheimer's disease pathology.
• Targeting GSK3β may be a viable therapeutic strategy for conditions involving p25 and tau hyperphosphorylation.