The goal of this proposal is to determine the extent to which neuronal RNA binding proteins (n-RBPs) are present in the nervous system, and to explore the role they play in both the development and function of the brain and in paraneoplastic neurologic disease (PND). PNDs are autoimmune disorders that are believed to be triggered when tumor cells express proteins that are normally made only in neurons. This is associated both with effective anti-tumor immunity and neurologic degeneration. A number of groups have identified n-RBPs by expression vector cloning of brain libraries utilizing antiserum from PND patients. Two distinct groups of n- RBPs have emerged from this work. The Hu family of genes are human homologues of the Drosophila Elav gene, and are also related to the Drosophila sex-lethal gene. Elav is essential for neurogenesis in Drosophila, and sex-lethal mediates alternative splicing in a sequence specific manner. The Nova family of genes are related to the hnRNP K, FMR- l (fragile-X) and yeast MER- l RBPs. FMR- l loss of function mutations result in mental retardation, and the MER-l gene regulates alternative splicing. However, aside from sequence homologies vaguely suggesting a possible role in alternative splicing, very little is known regarding the role of the n-RBP proteins in brain or tumors. We propose a three-fold approach to the study of n-RBPs associated with paraneoplastic neurologic disease. Descriptive studies will include a careful evaluation of the extent and expression of the n-RBP gene families. We will specifically correlate these findings with the neurologic symptoms of PND patients. Functional studies will be performed with the aim of identifying specific target RNAs bound by n-RBPs. Biologic studies will evaluate the role of these genes in mice. These studies will contribute to our understanding of the role of n-RBPs in the development and function of the nervous system, and will clarify their role in the pathophysiology of the PNDs, including their association with autoimmune neurologic disease.
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