ACTIVITY OF THE ALZHEIMERS DISEASE PRESENILIN PROTEIN

阿尔茨海默病早老素蛋白的活性

• 批准号: 2909680
• 负责人: Mark E Fortini
• 金额: $ 22.58万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2909680
• 关键词: Alzheimer's disease; Drosophilidae; amyloid proteins; developmental neurobiology; gene mutation; genetically modified animals; immunocytochemistry; posttranslational modifications; presenilin; protein structure function; retina

DESCRIPTION: Research proposed in this application seeks to identify new members of the Presenilin protein family and analyze their functions during development of the retina. The two known human Presenilins are highly related integral membrane proteins with seven putative transmembrane segments, and mutations in the two human presenilin genes are believed to account for over 90% of early-onset Alzheimer's disease. Although the biochemical activities of the Presenilin proteins are unknown, they may regulate the intracellular trafficking or processing of other proteins, such as the B-amyloid precursor protein (B-APP), which is processed to yield the major constituent of the amyloid neuritic plaques found in the brain tissues of Alzheimer's disease patients. Recently, a C elegans Presenilin protein, termed Sel-12, has been identified through genetic screens for modifiers of the Notch/Lin- 12 signaling pathway, which regulates numerous cell fate decisions during nematode development. The applicants preliminary studies have led to the isolation of a new member of the Presenilin protein family that displays 44-52% amino acid sequence identity to the human and nematode Presenilins. Specific aims of this proposal include the determination of the complete sequence and genomic organization of this new presenilin gene, the production of antibodies that recognize the encoded protein, and the isolation of mutations that disrupt the gene. Additional goals include a detailed analysis of the subcellular distribution and function of this new Presenilin in the highly polarized neuroepithelium of the developing retina. Further studies performed in mutant and transgenic retinal tissues will seek to clarify the possible involvement of Presenilin in Notch/Lin-12-mediated signaling and B-APP processing. A more long-term goal of this research is to use genetic strategies to elucidate the molecular mechanisms involving Presenilin protein activity. Screening for modifiers of Presenilin-associated phenotypes may ultimately identify interacting proteins and increase our understanding of the biochemical causes of early-onset Alzheimer's disease.

描述：本申请中提出的研究旨在确定新的 早老素蛋白家族的成员并分析其功能 视网膜的发育。 两种已知的人类早老素具有高度 具有七个假定跨膜的相关整合膜蛋白 据信，两个人类早老素基因的片段和突变 占早发性阿尔茨海默病的 90% 以上。 虽然 早老素蛋白的生化活性尚不清楚，它们可能 调节其他蛋白质的细胞内运输或加工，例如 作为 B-淀粉样蛋白前体蛋白 (B-APP)，经过加工可产生 脑组织中发现的淀粉样神经炎斑块的主要成分 阿尔茨海默病患者。 最近，一种秀丽隐杆线虫早老素蛋白， 被称为 Sel-12，已通过基因筛选鉴定出修饰因子 Notch/Lin-12 信号通路，调节多种细胞命运 线虫发育过程中的决定。 申请人初步研究导致新成员被隔离 显示 44-52% 氨基酸序列的早老素蛋白家族的成员 人类和线虫早老素的身份。 本次活动的具体目标 建议包括确定完整序列和基因组 这种新的早老素基因的组织，产生的抗体 识别编码的蛋白质，并分离破坏的突变 基因。 其他目标包括对亚细胞的详细分析 这种新的早老素在高度极化的分布和功能 发育中的视网膜的神经上皮。 进一步的研究进行于 突变和转基因视网膜组织将寻求澄清可能的情况 早老素参与 Notch/Lin-12 介导的信号传导和 B-APP 加工。 这项研究的一个更长远的目标是利用遗传 阐明早老素分子机制的策略 蛋白质活性。 筛选早老素相关修饰剂 表型可能最终识别相互作用的蛋白质并增加我们的 了解早发性阿尔茨海默病的生化原因。