APP-RELATED GENES AND ALZHEIMER'S DISEASE

应用程序相关基因和阿尔茨海默病

• 批准号: 2053162
• 负责人: RUDOLPH Emile TANZI
• 金额: $ 21.62万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-01-01 至 1996-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2053162
• 关键词: Alzheimer's disease; RNA splicing; aging; amyloid proteins; animal genetic material tag; chemical binding; clathrin; family genetics; fusion gene; gene induction /repression; genetic promoter element; human genetic material tag; human subject; human tissue; in situ hybridization; messenger RNA; molecular cloning; molecular site; nucleic acid sequence; phosphorylation; protein metabolism; reporter genes; structural genes; tissue /cell culture; transcription factor

Recent evidence indicates that the amyloid p protein precursor (APP) gene is a member of a highly conserved family of related genes. An APP-like gene (APPL) has been isolated from Drosophila and another has been reported in the form of a partial cDNA isolated from rat testes. More recently, our laboratory has isolated human cDNA clones encoding two novel APP-like proteins (amyloid precursor-like proteins, APLP1 and APLP2). These proteins are highly homologous to APP at the amino acid level. The beta-A4 domain is only partially conserved in APLP1 and APLP2, however, the remarkable degree of conservation of amino acid identity and specific domains within this protein family suggest that these proteins may share common functions, and, perhaps interact with common factors that are involved with protein processing and gene regulation. Based on our preliminary findings, we propose that production, maturation, and metabolism of APP, APLP1, and APLP2 in neurons in which these proteins appear to be co-expressed, may be critically balanced. We hypothesize that changes in the stoichiometry of APP, APLP1, and APLP2 message and/or protein effectively divert APP into alternative metabolic pathways including those predisposed toward amyloid formation. We have mapped the human APLP2 gene to chromosome 11, and the APLP1 gene to the proximal long arm of human chromosome 19 where a late-onset form of FAD has also been assigned making APLP an excellent candidate for this gene defect. We propose to further characterize APLP1 and APLP2 and isolate other members of the APP-like gene family, concurrently comparing gene expression, regulation, and processing of these proteins. We have chosen to explore the APLP family at the DNA, RNA and protein levels because we believe that the potential importance of these novel proteins in the etiology of Alzheimer's disease and aging deserves such a prompt overall assessment. We fully appreciate that comprehensive studies of expression, regulation and processing of the APLP family could each entail grant proposals of their own. Therefore, we have devised a set of experiments aimed at providing in a focused manner, critical data points in each of these areas of investigation. The ultimate goal of the experiments proposed is to provide a rudimentary data set assessing the potential roles played by the APLP gene family in the process of Alzheimer- and age-related neurodegeneration.

最近的证据表明淀粉样蛋白P蛋白前体（APP）基因 是高度保守的相关基因家族的成员。类似应用的 基因（Appl）已从果蝇中分离出来，另一个是 以从大鼠睾丸分离的部分cDNA的形式报告。更多的 最近，我们的实验室隔离了编码两种小说的人cDNA克隆 应用类蛋白（淀粉样蛋白前体样蛋白，APLP1和APLP2）。 这些蛋白质在氨基酸水平上与应用高度同源。这 beta-A4域仅在APLP1和APLP2中部分保存 氨基酸身份和特定的显着保存程度 该蛋白质家族中的域表明这些蛋白质可能共享 共同的功能，也许与常见因素相互作用 参与蛋白质加工和基因调节。基于我们 初步发现，我们建议生产，成熟和 这些蛋白质的APP，APLP1和APLP2的代谢 似乎是共同表达的，可能是非常平衡的。我们假设这一点 APP，APLP1和APLP2消息的化学计量法和/或 蛋白质有效地将应用转移到替代代谢途径中 包括那些倾向于淀粉样蛋白形成的。我们已经映射了 人类APLP2基因至染色体11，APLP1基因至近端长 人类19号染色体的臂，后期发作的时尚形式也已经 分配使APLP成为该基因缺陷的极好候选者。我们 建议进一步表征APLP1和APLP2并隔离其他成员 在类似应用的基因家族中，同时比较基因表达， 这些蛋白质的调节和加工。我们选择探索 DNA，RNA和蛋白质水平的APLP家族，因为我们认为 这些新型蛋白质在病因中的潜在重要性 阿尔茨海默氏病和衰老值得迅速的总体评估。 我们完全感谢对表达，调节的全面研究 APLP家族的处理可能需要 他们自己的。因此，我们设计了一套针对的实验 以重点的方式提供这些领域的关键数据点 调查。提出的实验的最终目标是 提供一个基本的数据集，评估 APLP基因家族在阿尔茨海默氏症和年龄相关的过程中 神经变性。