Cyclin-dependent kinase 5 (Cdk5), a small serine-threonine kinase is required for proper development of the mammalian nervous system, and abnormal activation of this kinase is involved in the pathogenesis of cytoskeletal abnormalities and neuronal death in neurodegenerative disorders. To be activated, Cdk5 has to associate with regulatory subunits, such as p35 or p39. The experiments of the present proposal are directed to analyze the participation of these two highly related Cdk5 activators in neuronal polarization and in B-amyloid induced neurodegeneration. The specific hypotheses to be tested are that: 1) p35 and p39 have different expression patterns and subcellular localization, targeting Cdk5 to different substrates and hence having different functional roles during neuronal development. In this regard, we specifically propose that p35 is mainly involved in the regulation of cytoskeletal dynamics during axon formation, while p39 in synaptogenesis; and 2) Activation of the MAPK pathway by extracellular matrix molecules, such as laminin, or by B-amyloid enhances Cdk5 activity by promoting the synthesis of p35 and/or p39. These experiments will be carried out using as a model system cultured hippocampal pyramidal and several state of the art techniques in cellular and molecular biology. The results that we expect to obtain will certainly contribute to a better understanding of the mechanisms underlying neurite polarization and degeneration in central neurons.
