PHOSPHORYLATION OF NEURONAL CYTOSKELETON IN NEURODEGENERATIVE DISEASES

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Phosphorylation process plays an important role in the structural organization of neuronal cytoskeleton. Synthesis, transport and assembly of neurofilament (NF) proteins are developmentally and spatially regulated by specific kinases that extensively phosphorylate different motifs such as Lys- Ser-Pro (KSP) repeats in the carboxyl-terminal tail domain of NF- M and NF-H. This phosphorylation stabilizes the NF network in the axon, and to affect the axonal transport and conduction velocity in the neurons. Cyclin dependent kinase-5 (Cdk5) is believed to phosphorylate KSP motifs in NF and tau protein. The later phosphorylation occurs exclusively at the same sites found in the tau protein from Alzheimer?s disease brain. Abnormal NF phosphorylation has also been associated with neuro-degenerative diseases. In order to delineate precise roles of specific kinases in neuro-degenerative process in vivo, we generated Cdk5 null mouse which exhibited abnormal corticogenesis associated with absence of cortical laminar structures and cerebellar foliation; degenrative changes in the large motor neurons in the brain stem and in the spinal cord with the abnormal accumulation of NF immunoreactivity. Subsequent analysis of Cdk5 null phenotype revealed a new cell-autonomous pathway through which Cdk5 exerts its effects on the neuronal migration and corticogenesis. Our recent studies indicate CNS-restricted role for Cdk5. The conditional knockout mice for Cdk5 were generated using Cre-plox system. These mice are grossly normal at birth, but exhibit unusual postures and movements indicating potential abnormalities in the peripheral nervous system. These mice are c