Neurofilaments are major proteins of the neuronal cytoskeleton, although their function is not well understood at present. They are unusual, compared to other intermediate filaments, in that they express considerable quantities of very heavily phosphorylated high molecular weight material, some of which is apparently associated with cross-bridging structures. I have demonstrated clear immunological differences between neurofilaments in axons and dendrites and between those of mature and developing regions of the nervous system. Such distributions suggest participation of neurofilaments in the mechanisms of development, plasticity and axon/dendrite differentiation. In addition changes in neurofilamentous organization are characteristic of common human pathologies, and may be implicated in Alzheimers disease.
The aims of this grant are 1. to examine the extent and significance of neurofilament phosphorylation using immunocytochemical approaches, and to assess the importance of this modification in the production of the immunological differences observed; 2. to identify, purify and characterize protein kinases responsible for this phosphorylation; 3. to study the cell type distribution of these kinases within the developing and mature nervous system; 4. to examine the relevance of neurofilament phosphorylation in the formation and control of neurofilament cross-links; 5. to assess the importance of neurofilament phosphorylation directly by microinjection of function blocking antibodies into cultured neurones; 6. to assess the effect of drugs known to cause neurofilamentous accumulations in vivo on the growth and morphology of cultured neurones; 7. to examine the effect of these drugs on described in vitro neurofilament-microtubule interactions. The work proposed will lead to an understanding of the control, extent and function of neurofilament phosphorylation and will test my hypothesis that drugs inducing neurofilamentous neuropathies act primarily on the heavily phosphorylated high molecular weight neurofilament proteins.
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