Abstract
Phosphorylation of cytoskeletal proteins is tightly regulated by the activities of multiple protein kinases and phosphatases. Three kinases, Cyclin-dependent kinase 5 (Cdk5), Glycogen synthase kinase 3β (GSK3β) and MAPKs have been implicated in their direct involvement in neuronal cytoskeletal protein phosphorylation. Cdk5 and GSK3β have been identified as prime candidates for pathogenesis. Cdk5 is a proline-directed serine/threonine protein kinase that requires an interaction with its activators, p35 or p39, to be catalytically active. While Cdk5 expression is ubiquitous, p35 and p39 are abundantly expressed in postmitotic neurons which, therefore, exhibit enhanced levels of Cdk5 activity. A pleiotropic kinase, Cdk5 has a multifunctional role in the mammalian central nervous system. Cdk5 was originally identified as a major Tau kinase. It associates with early stages of neurofibrillary tangles (NFTs). NFTs are composed mainly of hyperphosphorylated Tau aggregates, the pathological hallmarks of neurodegenerative tauopathies and Alzheimer’s disease (AD). Cdk5, by phosphorylating neuronal cytoskeletal proteins, such as Tau and neurofilaments (NFs), plays a critical role in neurodegeneration. In this review, we focus on the specific roles of Cdk5 phosphorylation of the neuronal cytoskeletal proteins (NFs and Tau) that contribute to neurodegeneration.
Published Version
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