Harish C. Pant, Ph.D.

The major focus of this laboratory has been to study the mechanisms of topographic regulation of neuronal cytoskeletal proteins regulation by phosphorylation and neurodegeneration. In a normal physiological state, cytoskeletal proteins are phosphorylated extensively in the axonal compartment of a mature neuron. Although all the substrates, kinases, phosphatases and their regulators are synthesized in neuronal cell bodies, little or no cytoskeletal protein phosphorylation has been detected in the cell body compartment. Under a variety of neuropathological conditions, however, such as ALS, Alzheimers Disease, or Picks disease, hyperphosphorylation of these molecules has been found in abnormal aggregates within cell bodies, usually correlated with massive neuronal cell death. The mechanisms underlying these profound compartmental shifts in neuronal phosphorylation are not well understood.The normal physiological processes within neurons are controlled by signal transduction mechanisms that regulate the balance between protein kinase and protein phosphatase activities. We have shown that the most abundant and extensively phosphorylated motifs in the c-terminal domains (lys-ser-pro-, or KSP) are primarily phosphorylated by proline directed kinases, cdk5 and MAP kinases. Moreover, we have demonstrated that this phosphorylation is due to activation of the signal transduction cascade. Recently, we have focussed on the other part of this regulation, the protein phosphatases. The other project is to study the expression, regulation and role of neuronal Cdk5 in nerve cell function.Cdk5 is a unique multifunctional kinase. Unlike other cyclin-dependent kinases, it is expressed predominantly in post-mitotic neurons, its activity modulated by association with nervous system-specific propeins. Since its identification and characterization in our laboratory, we have been intensively studying its mechanisms of regulation and its role in nerve cell function.