At the Fulcrum in Health and Disease: Cdk5 and the Balancing Acts of Neuronal Structure and Physiology

Abstract

Cdk5 has been implicated in a multitude of processes in neuronal development, cell biology and physiology. These influence many neurological disorders, but the very breadth of Cdk5 effects has made it difficult to synthesize a coherent picture of the part played by this protein in health and disease. In this review, we focus on the roles of Cdk5 in neuronal function, particularly synaptic homeostasis, plasticity, neurotransmission, subcellular organization, and trafficking. We then discuss how disruption of these Cdk5 activities may initiate or exacerbate neural disorders. A recurring theme will be the sensitivity of Cdk5 sequelae to the precise biological context under consideration.

Keywords: Cdk5; Cyclin-dependent kinase; Dendrite development; Neuronal structure; Synapse.

Figure 1. The lifecycle of Cdk5

Cdk5 kinase activity is initiated by binding to the myristoylated regulatory subunit, p35. Myristoylation links Cdk5/p35 to the plasma membrane, limiting the action of the complex to specific cellular compartments. Cdk5/p35 autophosphorylates, leads to ubiquitylation and degradation. Alternatively, p35 can be cleaved by calpain in response to elevated cytosolic Ca⁺² to produce Cdk5/p25. This form is resistant to degradation, and it lacks the myristoylation site, allowing the complex to dissociate from the membrane and interact with different targets.

Figure 2. Targets of Cdk5 at pre- and post-synaptic sites

Schematic representation of some binding partners and targets of Cdk5 at a glutamatergic synapse. Presynaptically, Cdk5/p35 interacts with SNARE proteins and their regulators such as Munc18 and syntaxin to facilitate neurotransmitter exocytosis. Synaptic proteins are recycled by dynamin-I and amphiphysin-I mediated endocytosis in clathrin-coated vesicles, and returned to the reserve or readily releasable synaptic vesicle pools. Cdk5 interacts with each of these proteins/receptor complexes. Postsynaptically, Cdk5 regulates NMDA/AMPA receptor clustering within the postsynaptic density through the scaffolding protein, PSD-95. Upon NMDA receptor activation p35 associates with CaMKIIα, potentially influencing signal transduction.

Figure 3. Roles of Cdk5 in neuronal structure and trafficking

Schematic of a typical neuron, with spatially localized Cdk5-regulated functions listed under the cellular compartment in which they occur. Symbols referring to specific molecular and cellular components are defined in the boxed key at the top. Microtubule polarity is indicated by (+) and (−) symbols. Note that positioning of the components in neuronal processes typically reflects a balance of anterograde and retrograde trafficking. Most components are therefore shown in association with both dynein and kinesin motors.