Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase with close structural homology to the mitotic Cdks. The multifaceted of Cdk5 and p35, the neuron-specific regulatory subunit of Cdk5, plays significant roles in brain growth, such as neuronal movement and neurite outgrowth. Cdk5 has an important role in the growth and maturity of the brain, and abnormal Cdk5 activity has been shown to cause the degeneration of neurons in neurodegenerative diseases including Alzheimer’s, Parkinson’s and Amyotrophic Lateral Sclerosis. Cdk5 has a multifarious nature that can be dangerous for neurons if its action is either highly decreased or increased (Lau et al, 2002).
According to Fatema and Mehdi (2008), “Cdk5 is activated by non-cyclin proteins, p35 and p39. Cdk5 has the function of phosphorylating a wide range of proteins most of which are associated with cell morphology and motility. A large number of known substrates of Cdk5 are cytoskeletal essentials that communicate with molecules or proteins that are involved in regulating its activity.” In cells without any defects, transcription and activity of Cdk5 are strictly controlled.
Cdk5 is found mostly in post-mitotic neurons, its natural activity is essential for migration and maturation of neurons in the developing brain. Components involved in the control of Cdk5 activities are well-thought-out as prospective therapeutic molecules for neurodegenerative diseases. Cyclin-dependent kinase 5 is mainly active in the central nervous system (CNS) due to the selective neuronal localization of its activator proteins, p35 and p39, or their truncated forms, p25 and p29 (Dhavan and Tsai, 2001). Cdk5 phosphorylates different types of substrates and therefore performs a crucial role in neuronal differentiation, migration, axon outgrowth and synaptogenesis (Lee and Kim, 2004; Smith et al., 2001).
However, increasing evidence has shown that abnormal activation of Cdk5 is toxic to neurons, leading to apoptosis under both physiological and pathological conditions (Shelton and Johnson, 2004). Defective Cdk5 activity culminates into hyperphosphorylation of tau and neurofilaments, leading to microtubule network damage and deterioration, neuronal retraction and apoptosis (Bu et al., 2002). Besides, Cdk5 arbitrates neurotoxic consequences through phosphorylation and prevention of the transcription element myocyte enhancer factor 2 (MEF2), one of the most important elements involved in regulation in neuronal survival (Tang et al., 2005).
The normal Cdk5 functions, conferred mainly by association with its primary activator p35, is vital for normal cellular actvities and must be tightly regulated. In cases of neurotoxicity, p35 is cleaved to form p25, which turns into a powerful and decentralised hyperactivator of Cdk5, this subsequently leads to down regulation of Cdk5 activity. p25 levels have been found to be elevated in ALS. p25/Cdk5 also causes excessive phosphorylation of neurofilament proteins that makeup pathological trait found in Parkinson’s disease and Amyotrophic Lateral Sclerosis (Tomizawa et al, 2002; Tian, Yang, & Mao, 2003).
Down regulation of Cdk5 is caused by removal of the first 98 amino acids of p35 by the Ca2+-dependent cysteine protease, calpain, leaving Cdk5 linked with the N-terminal truncated form p25. The cleavage of p35 to p25 damages the subcellular circulation of active Cdk5 from membranes to the cytosolic fraction, eventually interfering with substrate specificity. p25 accumulates in neurons undergoing various types of cell death. The appearance of Cdk5/p25 in cultured cells leads to increased phospho-Tau levels in relation to cells expressing Cdk5/p35. Additionally, exogenous overexpression of p25 results in a neurodegenerative phenotype including the formation of paired helical filaments, Tau aggregation, and neuronal loss similar to that observed in Alzheimer disease (Tang, 2005).
Cdk5/p25 has also been drawn in ischemia-induced neuronal loss in the hippocampus via increased phosphorylation of the NR2A subunit of the N-methyl-D-aspartic acid receptor. In addition, several recent reports indicate that Cdk5-p25 mediates cell death via translocation to the nucleus. Production of p25 potentiates nuclear Cdk5 activity in cultured neurons, facilitating phosphorylation and inhibition of the pro-survival transcription factor MEF2. Abnormal Cdk5 activity may also contribute to neuronal apotosis by way of phosphorylation of other survival factors such as the tumor suppressor protein p53 and retinoblastoma protein. (Smith et al, 2001).
References
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Dhavan, R., & Tsai, L. H., 2001. A decade of Cdk5. Nat. Rev. Mol. Cell Biol. (2), pp 749- 759.
Fatema, A. D. & Medhi, S. R. 2008. Biomedical and Life sciences. Journal of Molecular Neurobiology. (28), pp 351-369.
Lau, L. F., Seymour, P. A., Sanner, M. A. and Schachter, J. B., 2002. Cdk5 as a drug target for the treatment of Alzheimer’s disease. J. Mol. Neurosci. (19), pp 267-273.
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Tian, B., Yang, Q. & Mao, Z., 2003 Phosphorylation of ATM by CDk5 mediates DNA damage signaling and regulates neuronal death. Journal of Neuroscience (22), pp 2534-2540.
Tomizawa, K. & Matshusta, M. 2002. Cdk5/p35 phosphorylation and down regulation. Journal of Neuroscience (22), pp 2590-2597.