Peptides Derived from Neuronal Cell Cycle like Kinase 5 Activator p35, in Neurodegeneration; Pathology and Therapy

Normally, Cdk5 kinase, a Ser/Thr kinase of the cyclin dependent kinase family is essential for neuronal development, neuronal migration, cortical layering, synapse formation and behavioral functions [2]. The kinase targets a large number of neuronal protein substrates with proline directed Ser/Thr residues, which accounts, in part, for its importance in the nervous system. Its role stems from its regulation by neuronal-specific activators proteins, p35 and p39 instead of cyclins [3,4]. Cdk5, when isolated from the bovine brain is found in three states, as an large inactive complex in the cytoplasm, as an active Cdk5/p25 cytoplasmic complex and as part of a multimeric 650 kda complex bound to membranes by the p10, N-terminal myristolated domain of p35 [5] (Figure 1). In the brain, expression of p35 and p39 increases with development till adult; in fetus and adult p35 is phosphorylated by Cdk5 at Ser 8 which localizes a cytoplasmic Cdk5/p35 whereas in the fetus, phosphorylation of tyrosine 138 by tyrosine kinases, results in degradation of p35 via the proteosomeubiquitin pathway [4]. In the adult, however, Cdk5/p35 is restively more stable since neither site is phosphorylated as p35 acts to bundle microtubules and actin [6,7]. These regulatory options have profound effects on the role of Cdk5 in health and disease [8-11] (Figure 1).