ANALYSIS OF NEW DEGENERATION CAUSING MUTATIONS IN C ELEGANS

遗传性神经变性见于多种人类疾病。 为了了解突变是如何导致 对于神经细胞死亡，我们一直在研究线虫中的这种突变 秀丽隐杆线虫是一种生物，在这种生物中，先进的遗传和 分子分析是可能的。在过去，我们已经确定了一个家庭 基因的产物，即退化素，可以突变而导致神经 细胞死亡。在这项提案中，我们希望研究几个新的基因 也可以突变导致类似的死亡。这些新产品的数量 基因及其遗传特性表明，大多数基因并不在 退化素家族，应该为基因类型提供新的见解 这可能会导致遗传性神经退化。此外，还有几个 这些突变会导致感觉异常，我们假设 它们可能会通过改变所需的成分而导致退化 感觉传导。这项提案中的实验将检验这一点 假说，还有一个额外的好处，那就是它们可能允许我们识别 这样的组件。我们的具体目标是： 1.通过克隆基因组dna和对这些新基因进行分子鉴定。 至少其中三个人的DNA，分析了 导致退化的突变(通过对突变DNA进行测序)，以及 通过LacZ融合表达对产品进行本地化。 2.继续研究这些基因的基因特征 通过分析饱和突变来识别其他类型的基因 现有基因的无效表型，并通过获得和 其中一个突变deg(U662)的基因外抑制因子的特征 (我们已经确定了一个这样的基因)。 这个项目与健康的相关性源于 导致退化的突变。在基因被克隆之前，我们不会 知道是否有人类同源基因(更不用说它们是否是碱基了 任何人类疾病)。尽管如此，对这些基因的研究应该 突出遗传基础的细胞生物学过程 神经退行性疾病。

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.