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 Presenilin蛋白家族的成员并分析其功能 视网膜的发展。 两个已知的人类老龄素很高 具有七个推定跨膜的相关整合膜蛋白 据认为，两个人类presenilin基因的段和突变是 占早期晚期阿尔茨海默氏病的90％以上。 虽然 老年蛋白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贩运或加工，此类 作为B-淀粉样蛋白前体蛋白（B-APP），该蛋白被处理以产生 在脑组织中发现的淀粉样神经斑块的主要成分 阿尔茨海默氏病患者。 最近，一个C秀丽隐杆线虫蛋白， 已称为SEL-12，已通过遗传筛选确定 Notch/lin-12信号通路，调节许多细胞命运 线虫发展期间的决策。 申请人的初步研究导致了新成员的隔离 显示出44-52％氨基酸序列的Presenilin蛋白家族 对人和线虫presenilins的身份。 特定目的 建议包括确定完整序列和基因组 这种新的presenilin基因的组织，抗体的产生 识别编码的蛋白质以及破坏突变的隔离 基因。 其他目标包括对亚细胞的详细分析 该新老龄素在高度极化中的分布和功能 发育中的视网膜神经上皮。 进一步进行的研究 突变体和转基因视网膜组织将寻求阐明可能 培训蛋白参与Notch/Lin-12介导的信号传导和B-App 加工。 这项研究的更长期目标是使用遗传 阐明涉及保护素的分子机制的策略 蛋白活性。 筛选与老年蛋白相关的修饰符 表型最终可能识别相互作用的蛋白质并增加我们的 了解早期发作的阿尔茨海默氏病的生化原因。