Harish C. Pant
National Institute of Neurological Disorders and Stroke
Dr. Pant received his M.A. and Ph.D. degrees in Physics from Agra University, Agra, India. His postdoctoral studies were conducted on the mechanisms of electron and ion transport in model membrane systems at the Department of Biophysics at Michigan State University. He joined the Laboratory of Neurobiology in the NIMH as a senior staff fellow in 1974 with Dr. Ichiji Tasaki where he studied the function of the axonal cytoskeleton in the squid giant axon. In 1979 he moved to the NIAAA extending his studies on the neuronal cytoskeleton and the effects of alcohol on its regulation. Dr. Pant moved to the NINDS, Laboratory of Neurochemistry in 1987 where he is presently chief of the section on Cytoskeleton Regulation. His laboratory is studying the mechanisms of topographic regulation of neuronal cytoskeleton proteins by post-translational modification, including the role of kinase cascades in normal brain and during neurodegeneration.
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.