ACTIVITY OF THE ALZHEIMERS DISEASE PRESENILIN PROTEIN

描述：本申请中提出的研究旨在确定新的 早老素蛋白家族成员及其功能分析 视网膜的发育。已知的两种人类早老素是高度 具有7个可能跨膜的相关整膜蛋白 片段和两个人类早老素基因的突变被认为是 占早发性阿尔茨海默病的90%以上。尽管 早老素蛋白的生化活性尚不清楚，它们可能 调节细胞内其他蛋白质的运输或加工，如 作为B-淀粉样前体蛋白(B-APP)，它被加工成 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，一种线虫早老素蛋白， 命名为Sel-12的基因已通过基因筛查被鉴定为 调控众多细胞命运的Notch/Lin-12信号通路 线虫发育过程中的决定。 申请者的初步研究导致一名新成员被隔离 属于早老素蛋白家族，显示44%-52%的氨基酸序列 鉴定为人类和线虫的早老素。这一行动的具体目标 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，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极化人群中的分布和作用 发育中的视网膜的神经上皮。在美国进行的进一步研究 突变和转基因视网膜组织将寻求澄清可能的 早老素参与Notch/Lin-12介导的信号转导和B-APP 正在处理。这项研究的一个更长期的目标是使用基因 阐明早老素相关分子机制的策略 蛋白质活性。早老素相关修饰剂的筛选 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.