A NOVEL APPROACH TO INHIBIT THE DEREGULATION OF THE KINASES INVOLVED IN NEURODEGENERATIVE DISEASES
Harish C. Pant
NINDS, NIH, Bethesda, MD, USA
The Biology of Neurodegeneration program evolved from our laboratory studying the basic biology of neuronal cytoskeletal protein phosphorylation during development and normal function in the adult. To understand the molecular basis of neurodegeneration our major focus has been to study the regulation of compartment-specific patterns of cytoskeletal protein phosphorylation in neuronal perikarya and axons. We have demonstrated that phosphorylation of the numerous acceptor sites on such proteins as Tau and neurofilaments is tightly regulated topographically and generally confined to the axonal compartment. It is recognized that in neurodegenerative disorders such as Alzheimer’s disease (AD) and Amyotrophic lateral sclerosis (ALS), the pathology was characterized by an accumulation of aberrantly phosphorylated cytoskeletal proteins in cell bodies, suggesting that topographic regulation had been compromised. This led inevitably into studies of neurodegeneration in cell culture and model mice with emphasis on specific neuronal protein kinases, e.g. cyclin dependent kinase 5 (Cdk5), that targets numerous neuronal proteins including cytoskeletal proteins. The phosphorylation of these molecules is tightly and topographically regulated, which when deregulated, is responsible for the neuropathology seen in various neurodegenerative diseases. In cell systems, neuronal stress leads to deregulated kinases, for example, Cdk5, accompanied by abnormal cytoskeletal protein phosphorylation and cell death characteristic of neurodegeneration. Recently we have developed peptides derived from, p35, a neuron specific activator of Cdk5 for deregulated Cdk5 activity, which rescue the neurons from stress-induced pathology. The questions currently being investigated are (1) how is cytoskeletal protein phosphorylation topographically regulated in neurons?, (2) What factors are responsible for the regulation and deregulation of Cdk5 in neurons? and (3) How mouse models of AD and ALS be treated therapeutically with peptides that specifically inhibit deregulated Cdk5 inducing neuropathology?