ROLE OF TOPOGRAPHIC PHOSPHORYLATION IN THE NERVOUS SYSTEM
Harish C. Pant
NINDS, NIH, Bethesda, MD, USA
Brain is the most complex organism. It controls each and every activity of the human body. The past 20 years of research in neurobiology has increased in our knowledge of the basic molecular mechanisms of ageing. Most importantly, the rapid research advances in the identification of complex anatomical connections; increased understanding of the biochemical, molecular and genetic mechanisms. These processes that control brain structure and function, ability to measure and visualize our functioning during mental activity; and the capacity of monitoring many activities simultaneously in complicated network. There are several examples of central regulatory functions of the genes in the nervous system. The functional genetic analysis has identified signaling pathways that act as master regulators of ageing and lifespan and that are conserved in yeast, nematodes, flies and mammals. Analysis of these models suggests that the rate of ageing is not fixed but is plastic and open to modification. Similarly, memory deficits associated with our brain ageing also seems to be variable and possibly open to modification. An important question is whether age-related cognitive changes are mediated by any of the master regulators of ageing and lifespan identified in model organisms. Moreover, recent studies have implicated these pathways in the control of age-related brain pathology, raising the possibility that altered regulation of fundamental mechanisms of ageing may contribute to the pathogenesis of neurodegenerative disorders. The human brain, its afflictions and interventions are about its neurological issues. It also gives a background of normal functioning, its regulatory processes; biochemical, biological and physiological involved in development and ageing.
In this talk I will discuss the role of the Topographic regulation of phosphorylation in neurons. Within the last few years we have identified Pin1, a peptidyl-prolyl isomerase as a key modulator and stabilizer of compartment-specific phosphorylation regulated by kinases and phosphatases in neuronal perikarya and neurites. We have proposed that the hyper and aberrant phosphorylation of neuronal cytoskeleton proteins in the proline directed Ser/Thr residues by the activation of proline- directed kinases upon neuronal stress is stabilized by Pin1 in the cell bodies and leads to neuronal pathology typical of AD and ALS. We suggest that Pin1 and PP2A may be candidate targets for therapeutic intervention in neurodegenerative disorders. The presence of aberrant and hyperphosphorylated neurofilaments and tau protein in AD has been recognized as hall mark. The basic mechanisms of their regulation, physiology and deregulation, neurodegeneration will be the subject of my talk.