Cdk5 is a proline-directed Ser/Thr protein kinase predominantly expressed in postmitotic neurons together with its activator, p35. N-terminal truncation of p35 to p25 by calpain results in deregulation of Cdk5 and contributes to neuronal cell death associated with several neurodegenerative diseases. Previously we reported that p35 occurred as a phosphoprotein, phospho-p35 levels changed with neuronal maturation, and that phosphorylation of p35 affected its vulnerability to calpain cleavage. Here, we identify the p35 residues 138 predominantly defines the susceptibility of p35 to calpain-dependent cleavage and that dephosphorylation of this site is a critical determinant of Cdk5-p25-induced cell death associated with neurodegeneration. Cyclin-dependent kinase 5 (Cdk5)2 is a unique member of the Cdk family. Its activity in postmitotic neurons is completely dependent upon association with one of two neuronal specific activators, p35 or p39. Cdk5/p35 is involved in a panoply of processes critical to central nervous system function both during development and throughout maturity including neuronal migration during corticogenesis, neurite outgrowth, regulation of the synaptic vesicle cycle, neurotransmitter release, and postsynaptic neurotransmitter receptor regulation and signaling (1-3). The mechanisms by which Cdk5 activity is normally regulated remains to be fully delineated. Furthermore, because aberrant Cdk5 activity has been implicated in the etiology of neurodegenerative diseases (4, 5), identifying the biochemical mechanisms contributing to deregulation of Cdk5 is of substantial biomedical relevance.Deregulation of Cdk5 results from removal of the first 98 amino acids of p35 by the Ca 2ϩ -dependent cysteine protease, calpain, leaving Cdk5 associated with the N-terminal truncated form p25. Cleavage of p35 to p25 changes the subcellular distribution of active Cdk5 from membranes to the cytosolic fraction (6, 7), thereby altering substrate specificity. p25 accumulates in neurons undergoing various types of cell death (6 -9). Expression of Cdk5/p25 in cultured cells results in increased phospho-Tau levels in comparison to cells expressing Cdk5/ p35 (6). Furthermore, exogenous overexpression of p25 in transgenic mice results in a neurodegenerative phenotype including the formation of paired helical filaments, Tau aggregation, and neuronal loss similar to that observed in Alzheimer disease (10, 11).Cdk5/p25 has also been implicated in ischemia-induced neuronal loss in the hippocampus via increased phosphorylation of the NR2A subunit of the N-methyl-D-aspartic acid receptor (12). In addition, several recent reports indicate that Cdk5-p25 mediates cell death via translocation to the nucleus (13-15). p25 generation increases nuclear Cdk5 activity in cultured neurons, facilitating phosphorylation and inhibition of the pro-survival transcription factor MEF2 (13,15,16). Aberrant Cdk5 activity may also contribute to neuronal cell death via phosphorylation of other survival factors such as the tumor suppressor protein p53 ...

Cdk5 (cyclin-dependent kinase 5) activity is dependent upon association with one of two neuron-specific activators, p35 or p39. Genetic deletion of Cdk5 causes perinatal lethality with severe defects in corticogenesis and neuronal positioning. p35 -/-mice are viable with milder histological abnormalities. Although substantial evidence implicates Cdk5 in synaptic plasticity, its role in learning and memory has not been evaluated using mutant mouse models. We report here that p35 -/-mice have deficiencies in spatial learning and memory. Close examination of hippocampal circuitry revealed subtle histological defects in CA1 pyramidal cells. Furthermore, p35 -/-mice exhibit impaired long-term depression and depotentiation of long-term potentiation in the Schaeffer collateral CA1 pathway. Moreover, the Cdk5-dependent phosphorylation state of protein phosphatase inhibitor-1 was increased in 4-week-old mice due to increased levels of p39, which colocalized with inhibitor-1 and Cdk5 in the cytoplasm. These results demonstrate that p35-dependent Cdk5 activity is important to learning and synaptic plasticity. Deletion of p35 may shift the substrate specificity of Cdk5 due to compensatory expression of p39. Keywords: cyclin-dependent kinase 5, long-term depression, long-term potentiation, neuron-specific activators, synaptic plasticity. Address correspondence and reprint requests to Toshio Ohshima, Laboratory for Developmental Neurobiology, Brain Science Institute, RIKEN, Wako, Saitama 351-0198, Japan. E-mail: ohshima@brain.riken.go.jpAbbreviations used: Cdk5, cyclin-dependent kinase 5; EPSP, excitatory postsynaptic potential; fEPSP, field EPSP; LFS, low-frequency stimulation; LTD, long-term depression; L-LTP, Long-lasting-LTP; LTP, long-term potentiation; P, postnatal day; YFP, yellow fluorescent protein.

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