ANALYSIS OF NEW DEGENERATION CAUSING MUTATIONS IN C ELEGANS

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Inherited neurodegeneration is seen in a wide variety of human diseases. To gain an understanding of the molecular bases of how mutations can lead to nerve cell death, we have been studying such mutations in the nematode Caenorhabditis elegans, an organism in which advanced genetic and molecular analyses are possible. In the past we have identified a family of genes whose products, the degenerins, can be mutated to cause nerve cell death. In this proposal we wish to study several new genes that also can be mutated to cause similar deaths. The number of these new genes and their genetic properties suggest that most are not in the degenerin family and should provide new insights into the type of genes that can lead to inherited neurodegeneration. In addition, several of the mutations lead to sensory abnormalities, and we have hypothesized that they may cause degeneration by altering components needed for sensory transduction. The experiments in this proposal will test this hypothesis, with the added benefit that they may allow us to identify such components. Our specific aims are: 1. to characterize molecular these new genes by cloning genomic DNA and cDNAs for at least three of them, analyzing the nature of the degeneration-causing mutations (by sequencing mutant DNAs), and localizing the products by lacZ fusions expression. 2. to continue the genetic characterization of these genes by doing saturation mutageneses to identify other genes of this type, by analyzing the null phenotype of the existing genes, and by obtaining and characterizing extragenic suppressor of one of the mutations, deg(u662) (we have identified one such gene already). The health relatedness of this project stems from the nature of the degeneration-causing mutations. Until the genes are cloned, we will not know whether there are human homologues (much less whether they are bases of any human diseases). Nonetheless, the study of these genes should highlight cell biological processes underlying inherited neurodegenerative disorders.