Cdk5: multitasking between physiological and pathological conditions

Cyclin-dependent kinase 5 (Cdk5) is a peculiar proline-directed serine/threonine kinase. Unlike the other members of the Cdk family, Cdk5 is not directly involved in cell cycle regulation, being normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity. This kinase is present mainly in post-mitotic neurons and its activity is tightly regulated by the interaction with the specific activators, p35 and p39. Despite its pivotal role in CNS development, Cdk5 dysregulation has been implicated in different pathologies, such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and, most recently, prion-related encephalopathies (PRE). In these neurodegenerative conditions, Cdk5 overactivation and relocalization occurs upon association with p25, a truncated form of the normal activator p35. This activator switching will cause a shift in the phosphorylative pattern of Cdk5, with an alteration both in targets and activity, ultimately leading to neuronal demise. In AD and PRE, two disorders that share clinical and neuropathological features, Cdk5 dysregulation is a linking event between the major neuropathological markers: amyloid plaques, tau hyperphosphorylation and synaptic and neuronal loss. Moreover, this kinase was shown to be involved in abortive cell cycle re-entry, a feature recently proposed as a possible step in the neuronal apoptosis mechanism of several neurological diseases. This review focuses on the role of Cdk5 in neurons, namely in the regulation of cytoskeletal dynamics, synaptic function and cell survival, both in physiological and in pathological conditions, highlighting the relevance of Cdk5 in the main mechanisms of neurodegeneration in Alzheimer's disease and other brain pathologies.