NEURAL HOMOLOG OF AMYLOID PROTEIN PRECURSOR

阿尔茨海默病最显著的特征是加速 脑沉积中淀粉样蛋白的出现。体内的β淀粉样多肽 这些沉淀物是从一种更大的蛋白质--β淀粉样蛋白中分解出来的。 前体(APP)。目前的数据表明，APP显示出一种异常 阿尔茨海默氏症患者大脑中的代谢命运。应用程序 基因编码了一个蛋白质家族，它表现出无处不在的分布， 然而，APP695的一种形式是神经系统特有的。一只果蝇 基因APPL(淀粉样蛋白前体)编码一种蛋白质APPL，它可以 与神经系统特有的形式显示出惊人的序列同源性 应用程序。氨基酸序列、生物发生和空间分布的相似性 时间分布导致了APPL是一种 果蝇神经特异性APP695的同源物，以及进一步的APP 和APPL在神经系统内提供类似的重要功能。 拟议的实验旨在验证这些假设，并 阐明APPL在体内的作用。这些实验将使用分子 接近并将利用可能的遗传操作 在果蝇中创造体外新的App1基因突变体。在……里面 体外突变的App1基因将被引入苍蝇基因组。这个 APP1缺失突变体的表型及新创突变体 将被分析；APPL和突变APPL形式的生物发生将被分析 在细胞培养和体内研究；以及生物功能形式 APPL蛋白的结构域和蛋白中的结构域将被定义。 人-蝇嵌合基因将在体内功能测试中进行测试。 与APPL相互作用的基因将被定义为一种获得彻底 了解APPL所从事的生物过程。这个 拟议的分析可能有助于理解 APP在正常状态下的功能和代谢 退行性疾病状态。

The most striking feature of Alzheimer's disease is the accelerated appearance of amyloid in brain deposits. The beta amyloid peptide in these deposits is cleaved from a larger protein, beta amyloid protein precursor (APP). Current data suggest that APP displays an aberrant metabolic fate in brains afflicted with Alzheimer's condition. The APP gene encodes a family of proteins that shows ubiquitous distribution, however one form of APP, APP695 is nervous system-specific. A Drosophila gene Appl (Amyloid protein precursor-like) encodes a protein, APPL, that shows striking sequence homology to the nervous system-specific form of APP. Similarities of amino acid sequence, biogenesis, and spatial and temporal distribution have led to the hypothesis that APPL is a Drosophila homolog of neural-specific APP695, and furthermore that APP and APPL provide similar important functions within the nervous system. The proposed experiments are designed to test these suppositions and elucidate the in vivo role of APPL. These experiments will use molecular approaches and will take advantage of the genetic manipulations possible in Drosophila to create in vitro novel mutants in the Appl gene. In vitro mutated Appl genes will be introduced into the fly genome. The phenotype of Appl deletion mutants and the newly created novel mutants will be analyzed; the biogenesis of APPL and of mutant APPL forms will be studied in cell culture and in vivo; and biologically functional forms of the APPL protein and domains within the protein will be defined. Human-Fly chimeric genes will be tested in the in vivo functional assays. Genes that interact with Appl will be defined as a way to gain a thorough understanding of the biological processes that, APPL is engaged in. The proposed analysis can potentially contribute to the understanding of the function and metabolism of APP under normal conditions and in the degenerative disease state.