A Tale of the Good and Bad: Remodeling of the Microtubule Network in the Brain by Cdk5

Abstract

Cdk5, a cyclin-dependent kinase family member, is a global orchestrator of neuronal cytoskeletal dynamics. During embryogenesis, Cdk5 is indispensable for brain development. In adults, it is essential for numerous neuronal processes, including higher cognitive functions such as learning and memory formation, drug addiction, pain signaling, and long-term behavior changes through long-term potentiation and long-term depression, all of which rely on rapid alterations in the cytoskeleton. Cdk5 activity becomes deregulated in various brain disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, attention-deficit hyperactivity disorder, epilepsy, schizophrenia, and ischemic stroke; these all result in profound remodeling of the neuronal cytoskeleton. This Commentary specifically focuses on the pleiotropic contribution of Cdk5 in regulating neuronal microtubule remodeling. Because the vast majority of the physiological substrates of Cdk5 are associated with the neuronal cytoskeleton, our emphasis is on the Cdk5 substrates, such as CRMP2, stathmin, drebrin, dixdc1, axin, MAP2, MAP1B, doublecortin, kinesin-5, and tau, that have allowed to unravel the molecular mechanisms through which Cdk5 exerts its divergent roles in regulating neuronal microtubule dynamics, both in healthy and disease states.

Keywords: Alzheimer disease; Cdk5; Cytoskeleton; Microtubules; Neurodegeneration; p25; p35.

Fig. 1. Components of neuronal cytoskeleton

The neuronal cytoskeleton is composed of actin filaments (red), microtubules (MTs; green) and neurofilaments (NFs; purple). The axonal growth cone is comprised of lamellipodia and filopodia, and is highly enriched in actin filaments. Lamellipodia consist of a dense F-actin network, and filopodia contain bundled F-actin, whereas MTs emanate from axons. Axonal microtubules have an unidirectional arrangement with their plus ends facing the axon tip, thus facilitating directional axonal growth, whereas dendritic microtubules have a mixed orientation. NFs are highly enriched in the axons and maintain axonal integrity, caliber and conduction velocity. MTs are approximately three times thicker in diameter compared to NFs, which are three times thicker than actin.

Fig. 2. Cdk5-mediated regulation of MT dynamics and axonal growth

Cdk5 regulates MTs dynamics by phosphorylating several MT-associated proteins (MAPs), such as p35, CRMP2, axin, stathmin, doublecortin, TPPP, tau, and MAP1B. As shown on the left, Cdk5 phosphorylates p35 at T138 in fetal brains, which inhibits its MT polymerization activity and results in the dynamic reorganization of the MT architecture. Furthermore, Cdk5 regulates CRMP2 through several direct and indirect mechanisms (shown in the middle). Direct phosphorylation of CRMP2 by Cdk5 primes it to be phosphorylated by GSK3β, which inactivates CRMP2, resulting in growth cone collapse. Indirectly, Cdk5 activates CRMP2 by phosphorylating Axin and GSK3β. Phosphorylated axin binds to GSK3β, which inhibits its activity. Cdk5 also directly inhibits GSK3β through phosphorylation, which increases the pool of non-phosphorylated, active CRMP2, thus promoting axonal growth. Cdk5 increases the pool of acetylated α-tubulin by inhibiting SIRT2 resulting in MT stability and axonal growth. Moreover, Cdk5-mediated phosphorylation of stathmin prevents sequestration of free tubulin, facilitating axonal growth (shown on the right). Cdk5-mediated phosphorylation of MAP1B enhances its MT-binding affinity, whereas Cdk5-mediated phosphorylation of doublecortin, tau and TPPP lower their affinity towards MTs. Red and green arrows represent activating and inactivating pathways, respectively.

Fig. 3. Role of Cdk5 in neuronal migration

Cdk5-mediated phosphorylation of ErbB4 activates PI3K/Akt pathway leading to tangential migration of interneurons toward and within the cerebral cortex. Cdk5 promotes nucleokinesis by phosphorylating FAK at S732. Phosphorylation of FAK by Cdk5 is believed to promote the proper organization of MTs that link the nucleus and the centrosome, thereby facilitating nucleokinesis and thus neuronal migration. During neocortical development, Cdk5, through DISC1, attenuates the proliferation of progenitor cells, while concurrently directing them towards correct locations by increasing neuronal migration. Cdk5 phosphorylates DISC1 at Ser713, which increases its affinity towards BBS1 and BBS4, resulting in increased neuronal migration. Cdk5 also indirectly regulates DISC1-mediated neuronal migration by phosphorylating Dixdc1at Ser250, which facilitates the formation of the DISC1-Dixdc1-Ndel1 complex that is essential for neuronal migration as it modulates the actin and MT cytoskeleton. In granular neurons, Cdk5 employs an indirect mechanism to activate Ndel1. Cdk5 activates Aurora A kinase through Cdk5-RAP2, which in turn phosphorylates Ndel1, resulting in MT remodeling and neuronal migration. In addition, Cdk5-mediated phosphorylation of Drebrin at Ser142 enables it to couple dynamic MTs to F-actin through MT-binding +TIP protein EB3 in growth cone resulting in increased neuronal migration.

Fig. 4. Cdk5-mediated regulation of axonal transport

Cdk5 orchestrates anterograde and retrograde axonal transport by regulating kinesin and dynein, respectively. Cdk5 drives kinesin-induced axonal transport by inhibiting GSK-3β activity and facilitates dynein function by phosphorylating Ndel1, thereby strengthening its interaction with Lis1. Ndel1 and Lis1 both bind to dynein and stimulate its cargo transport capacity. Cdk5 also regulates the rate and directionality of neuronal growth and migration by inducing the association of kinesin-5 with MTs through phosphorylation of Thr926.

Fig. 5. Reduced activity and hyperactivity of Cdk5 are each potentially neurotoxic

In healthy cells, Cdk5 activity is exquisitely controlled. Increase in Cdk5 activity or loss of Cdk5 activity, both can give rise to neurodevelopmental or neurological disorders.