Title: A novel translational approach to Neurodegenerative diseases?

Biography:

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.

Abstract

A novel translational approach to Neurodegenerative diseases.

Peptides  (TFP5/TP5) derived from neuronal cell cycle like kinase (Cdk5) activator, p35,  prevent  AD , ALS and PD  phenotypes in mice models; Protective and Restorative roles of TFP5/TP5 

Harish. C. Pant; Chief, Cytoskeletal Protein Regulation Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892. USA.

During our studies on the compartment specific phosphorylation of cytoskeletal proteins in the neurons, we discovered a novel kinase, Cdk5, a Cell Cycle dependent like kinase in the brain. Though it binds with cyclins, however, its activity is primarily restricted to neurons due to its binding and regulation by neuron specific proteins p35kDa and p39kDa. Cdk5, by virtue of its tight regulation, multifunctional role in neuronal development, migration, synaptogenesis and survival (it targets a large number of different types of neuronal processes), has emerged as a major player in nervous system function in health and disease. Our studies continue to unravel the role of Cdk5 in neurogenesis and synaptic function but our most exciting recent results have been related to its role in neurodegeneration and our success in developing compounds that protect neurons from deregulated Cdk5 pathology , neuro-inflammation, and apoptosis in vitro and in AD, PD and ALS and other neurodegenerative disease model mice. Hence, our current and future plans include a major emphasis on the efficacy of our newly modified peptide TFP5 (carrying a fluorescent marker at the N-terminal end and a TAT PTD sequence at the C-terminal (to facilitate penetration into tissues) and pass blood brain barrier, as a therapeutic candidate for AD, ALS and PD using model mice. Currently, most therapeutic approaches targeting the deregulated Cdk5/p25 complex in neurodegenerative disorders have focused primarily on drugs like roscovitine that inhibit Cdk5 activity by interfering with the ATP binding domain of the kinase. Most of these drugs, however, lack sufficient specificity, since all kinases including cell cycle Cdks, are vulnerable at the ATP binding site targeted by these drug molecules. In previous studies we identified a 126 residue truncated fragment, CIP, derived from the p35 activator, that specifically inhibited hyperactive Cdk5/p25 and rescued cortical cells in vitro from abnormal AD-like phenotypes. It did this without affecting the function of the normal Cdk5/p35. To study the role of CIP in vivo, we generated transgenic (Tg) CIP mice inducing CIP gene expression and cross them with p25Tg mice inducing p25 expression, AD model mice. The AD phenotypes were reduced in the tetra transgenic mice (CIPTg X p25Tg). These studies raised the exciting possibility that CIP might be a therapeutic candidate for the treatment of AD and other neurodegenerative disorders in which hyperactive Cdk5 was implicated. However, CIP is a 126 amino acid peptide too large for therapeutic interventions. Therefore we truncated CIP to a smaller peptide with 24 amino acid residues, (P5) and modified with higher efficacy to inhibit Cdk5 hyper activation. The modified P5 peptide, TFP5, crosses the BBB and is most effective in preventing the Alzheimer’s disease like phenotypes in vitro and in vivo (AD model mice) without toxicity. This talk will focus on the role of TFP5 peptide as a therapeutic reagent for AD , PD and ALS.