The roles of Cdk5 in neuronal development and neurodegeneration

Cyclin dependent kinase 5, Cdk5, is a small proline directed serine/threonine kinase. Although Cdk5 was discovered by its homology to Cdc2, it is not a typical Cdk. By virtue of expression of its activators, p35 and p39, Cdk5 is only active in the nervous system. Given its expression pattern, studies were initiated to determine the roles of Cdk5 in neuronal development and neurodegeneration.; The data show a surprising and novel role for Cdk5 in cell cycle control in the developing cerebral cortex. Loss of Cdk5 by genetic inactivation leads to loss of cell cycle regulation in post-mitotic neurons of the developing cortex. Additional studies indicated that not only is Cdk5 necessary and sufficient for cell cycle arrest, but it is necessary for neuronal differentiation both in vivo and in vitro. Further, Cdk5 expression but not kinase activity is required for cell cycle regulation; while the kinase activity is required for neuronal differentiation in vitro. Finally, the data indicate that cells that re-enter the cell cycle subsequently die.; Given its role in development further studies were initiated to determine the role Cdk5 exerts in neuronal death. It has been proposed that Cdk5 has a negative role in neurodegeneration via its kinase activity on the tau protein. Cdk5 hyperactivity is thought to lead to tau hyperphosphorylation and subsequent cell loss. Based on the developmental data, we hypothesized that changes in Cdk5 subcellular localization would affect cell cycle control, as well as tau phosphorylation in an in vitro model of Alzheimer's disease. The data show that even in the absence of Cdk5 there is continued tau phosphorylation in pathological conditions.; The data also show another role for Cdk5 in neurodegeneration. Cdk5 moves out of the nucleus in cortical neurons exposed to Abeta, the suspected neurotoxin in Alzheimer's disease. When it is lost from its nuclear location there is a concurrent re-entry into the cell cycle by post-mitotic neurons, as well as tau phosphorylation. We propose that these events ultimately lead to neuronal loss seen in AD.