NEURAL HOMOLOG OF AMYLOID PROTEIN PRECURSOR

老年痴呆症最显著的特征是 脑沉积物中淀粉样蛋白的出现。 β淀粉样肽 这些沉积物是从一种较大的蛋白质--β淀粉样蛋白--上切割下来的 前体（APP）。 目前的数据表明，APP显示出一种异常的 阿尔茨海默病患者大脑的代谢命运。 该应用程序 基因编码一个蛋白质家族，该家族显示出普遍存在的分布， 然而APP一种形式，APP 695是神经系统特异性的。 果蝇 基因Appl（淀粉样蛋白类转运蛋白）编码蛋白APPL，其 显示出与神经系统特异性形式的 附录 氨基酸序列、生物起源、空间和 时间分布导致假设APPL是一个 神经特异性APP 695的果蝇同源物，此外，APP 和APPL在神经系统内提供类似的重要功能。 拟议的实验旨在测试这些假设， 阐明APPLE的体内作用。这些实验将使用分子 并将利用可能的基因操作 在果蝇中产生Appl基因的体外新突变体。 在 将体外突变的App 1基因引入果蝇基因组。 的 Appl缺失突变体和新产生的新突变体的表型 将进行分析; APPL和突变APPL形式的生物起源将 在细胞培养和体内研究;和生物功能形式 将定义APPL蛋白质的结构域和蛋白质内的结构域。 将在体内功能测定中测试人-蝇嵌合基因。 与Appl相互作用的基因将被定义为一种获得彻底的 了解APPL所从事的生物过程。 的 拟议的分析可能有助于了解 APP在正常条件下和在 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.