BETA-AMYLOID PRECURSOR-LIKE GENE IN C. ELEGANS

致密斑块的沉积和神经原纤维缠结的存在 阿尔茨海默病确诊的两个尸检标准 疾病。致密斑块的主要成分是大约40个氨基酸。 来源于较大的淀粉样蛋白的酸性β-淀粉样多肽 前体(APP)。两个与APP相关的基因，它们编码具有 在人类中发现了与APP广泛同源的序列，并 APP基因家族的成员；然而，这些与APP相关的基因 而不是编码β-淀粉样多肽。停用一款果蝇应用程序- 相关基因导致可部分挽救的行为缺陷 通过人类APP转基因，表明APP和APP相关蛋白可能 有一种保守的功能，通过进化独立于 β淀粉样多肽。APP的正常功能和APP相关的 人们对蛋白质的了解仍然很少。我们有兴趣研究 功能，并正在通过识别APP来解决这个问题- 一种简单的模式系统--线虫--线虫的相关基因 优雅女装。华南虎的实验优势在于它很容易 在基因和分子上进行操控。我们已经鉴定出一种塞勒坎 APL-1基因，编码一种APP相关蛋白。推定的翻译 APL-1的产物与APP家族蛋白有很强的序列同源性。 我们已经鉴定了APL-1基因，测序并测定了它的 APL-I基因的染色体定位，并开始产生抗体 针对APL-1蛋白及其不同的结构域。我们建议1) 通过转座子插入突变鉴定APL-I基因突变； 2)通过行为学和形态学分析确定APL-1的功能； 3)通过抑制子分析确定与APL-I相互作用的基因； 检测APL-1过表达的影响。APL-1的特性研究 将深入了解这种与APP相关的蛋白质的功能，并将 识别与APL-1相互作用的基因。此外，确定一个 线虫APL-1蛋白的功能可能为了解 APP在高等动物(如人)中的功能和调节。

Deposition of dense plaques and the presence of neurofibrillary tangles are two postmortem criteria used in the definitive diagnosis of Alzheimer's disease. The major component of the dense plaques is an about 40 amino acid beta- amyloid peptide that is derived from a larger amyloid protein precursor (APP) . Two APP-related genes, which encode proteins with extensive sequence homology to APP, have been found in humans, and are members of the APP family of genes; these APP-related genes, however, do not encode the beta-amyloid peptide. Inactivation of a Drosophila APP- related gene results in behavioral deficits that can be partially rescued by a human APP transgene, suggesting that APP and APP-related proteins may have a conserved function through evolution that is independent of the beta-amyloid peptide. The normal function of APP and the APP-related proteins are still poorly understood. We are interested in studying the function of APP, and are approaching this problem by identifying APP- related genes in a simple model system, the nematode Caenorhabditis elegans. C. eiegans has the experimental advantages of being easy to manipulate genetically and molecularly. We have identified a C. eleqans gene, apl-1, that encodes an APP-related protein. The putative translation product of apl-1 has strong sequence homology with the APP family proteins. We have characterized an apl-1 cDNA, sequenced and determined the chromosomal location of the apl-I gene, and begun to generate antibodies against the APL-1 protein and its different domains. We propose to 1) identify mutations in the apl-I gene by transposon-insertion mutagenesis; 2) determine a function for APL-1 by behavioral and morphological assays; 3) identify genes that interact with apl-I by suppressor analysis; and 4) determine the effect of overexpression of apl-1. Characterization of apl-1 will yield insights into the function of this APP-related protein, and will identify genes that interact with apl-1. Furthermore, determining a function for the C. elegans APL-1 protein is likely to give clues into the function and regulation of APP in higher animals, such as man.