Taming hyper-active Cdk5: Disrupting the Cdk5-p25 axis as a therapeutic avenue for neurodegeneration and beyond.

Cyclin-dependent kinase 5 (Cdk5) is essential for neuronal development and synaptic function when activated by its physiological cofactors p35 and p39. Pathological calpain cleavage of p35 generates the more stable fragment p25, producing a hyperactive, mislocalized kinase complex that has been implicated in tau hyperphosphorylation, DNA damage, neuroinflammation, and aberrant neuronal cell-cycle re-entry. Three decades of work position the Cdk5-p25 axis as a convergent pathogenic mechanism in A...