ACTIVITY OF THE ALZHEIMERS DISEASE PRESENILIN PROTEIN

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，并分析它们在 视网膜的发育。 两种已知的人类早老素是高度 具有7个假定跨膜的相关整合膜蛋白 两个人类早老素基因的突变被认为 占早发性阿尔茨海默病的90%以上。 虽然 早老素蛋白的生物化学活性是未知的，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-淀粉样前体蛋白（B-APP），其被加工以产生 在脑组织中发现的淀粉样神经炎斑块的主要成分 老年痴呆症患者。 最近，一种秀丽隐杆线虫早老素蛋白， 被称为Sel-12，已经通过遗传筛选确定了修饰剂， Notch/Lin- 12信号通路，调节许多细胞命运 在线虫发育过程中的决定。 申请人的初步研究导致了一个新成员的隔离 显示44-52%氨基酸序列的早老素蛋白家族的 与人和线虫早老素的同一性。 具体目标 建议包括确定完整的序列和基因组 这种新的早老素基因的组织，抗体的产生， 识别编码的蛋白质，并分离出突变， 基因 其他目标包括详细分析亚细胞 这种新的早老素在高度极化的 发育中的视网膜的神经上皮。 在以下国家进行的进一步研究 突变体和转基因视网膜组织将试图澄清可能的 早老素参与Notch/Lin-12介导信号传导和B-APP 处理. 这项研究的一个更长期的目标是利用基因 阐明早老素分子机制的策略 蛋白活性 筛选早老素相关的调节剂 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。

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.