Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration

Abstract

Cyclin-dependent kinase 5 (Cdk5) is required for proper development of the mammalian central nervous system. To be activated, Cdk5 has to associate with its regulatory subunit, p35. We have found that p25, a truncated form of p35, accumulates in neurons in the brains of patients with Alzheimer's disease. This accumulation correlates with an increase in Cdk5 kinase activity. Unlike p35, p25 is not readily degraded, and binding of p25 to Cdk5 constitutively activates Cdk5, changes its cellular location and alters its substrate specificity. In vivo the p25/Cdk5 complex hyperphosphorylates tau, which reduces tau's ability to associate with microtubules. Moreover, expression of the p25/Cdk5 complex in cultured primary neurons induces cytoskeletal disruption, morphological degeneration and apoptosis. These findings indicate that cleavage of p35, followed by accumulation of p25, may be involved in the pathogenesis of cytoskeletal abnormalities and neuronal death in neurodegenerative diseases.

p53, Apaf-1, caspase-3, and -9 are dispensable for Cdk5 activation during cell death

“…Inhibition of calpain activation, which blocks p25 production and Cdk5 activation, prevents neuronal cell death. 29,31,32,35,41,42 Here we document the generation of p25 during cell death, as we had previously suggested. 28 We also establish that calpainmediated Cdk5/p25 activation coincides with cell death in both non-neuronal and neuronal systems, suggesting the generality of the role of Cdk5 in cell death.…”

“…Induction of p25 is a reliable indicator and measure of Cdk5 activation. 28,29,31 In A9, it took 12 h to activate caspase-3 ( Figure 2B, a) and induce p25 (Cdk5 activation - Figure 2B, b). As expected, the level of Cdk5 protein was constant for the 18 h in both C8 and A9 ( Figure 2B, c, data for 8, 15, and 18 h not shown).…”

“…The association between Cdk5 activation and cell death is seen in pathology: rat lungs infected with Streptococcus pneumoniae, 25 mouse limbs infected with Leishmania major, 26 preterm lamb lungs after ventilation, 27 cyclophosphamide-treated mouse embryos, 28 and several neurodisorders and neuronal injuries. [29][30][31][32][33][34][35][36][37] The regulatory signals and mechanisms by which Cdk5 is activated remain undefined.…”

Cyclin-dependent kinase-5 prevents neuronal apoptosis through ERK-mediated upregulation of Bcl-2

“…5 Cdk5 kinase activity has been implicated in neuronal death and survival. Amyloid b-peptide 6 and ischemic insults 7 induce the conversion of p35 to its truncated form p25, which causes apoptotic death of neurons. In contrast, the association of p35 and Cdk5 is required for neuronal survival and is involved in many processes in neuronal differentiation and functions most notably neurite outgrowth, 8 cortical lamination, 9 neuronal migration, 10 motility and adhesion.…”

Cloning and characterization of human IC53-2, a novel CDK5 activator binding protein

“…Conversion of p35 to p25 causes prolonged activation of CDK5. Moreover, expression of p25/ CDK5 complex in cultured primary neurons induces cytoskeletal disruption and apoptosis [18]. IC53-2 can bind to the fragment encoding the C-terminal p25 protein and not the N-terminal region p10.…”