PRESENILINS, APOPTOSIS AND AMYLOID BETA PROTEIN

大多数早发性家族性阿尔茨海默病(AD)病例是由高度相关的基因早老素-1(PS1)、早老素-2(PS1)和早老素-2(PS2)突变引起的，这些基因编码的是具有6到8个跨膜结构域的完整膜蛋白。由于早老素突变是遗传性早发性阿尔茨海默病的主要原因，了解早老素的正常功能以及这些蛋白的突变如何导致阿尔茨海默病是阿尔茨海默病研究的核心问题。在AD方面，早老素活性的两个方面受到了特别的关注。首先，突变的早老素已被证明可以改变更长且潜在更具致病性的淀粉样蛋白Aβ多肽变体(即Abeta1-42/43)的相对水平。其次，突变型早老素已被证明可以促进细胞凋亡。关于早老素在细胞凋亡中的作用，有证据表明PS2COOH端与未知蛋白(S)之间的蛋白质-蛋白质相互作用是导致细胞凋亡的激活原因。这项建议侧重于鉴定与早老素的COOH端相互作用的蛋白(S)，介导它们对细胞凋亡的影响，并可能改变较长的Aβ变异体的相对水平。其具体目的如下：1)鉴定和鉴定与早老素COOH端相互作用的蛋白质；2)研究相互作用蛋白(S)在早老素介导的细胞凋亡中的作用；3)分析相互作用蛋白(S)在早老素介导的较长的Aβ变异体增加中的作用；以及4)阐明早老素介导的细胞凋亡和早老素介导的较长的Aβ变异体增加的关系。

The majority of early-onset familial Alzheimer disease (AD) cases are caused by mutations in the highly related genes presenilin-1 (PS1) and presenilin-2 (PS1) and presinilin-2 (PS2) which encode what are predicted to be integral membrane proteins with six or eight membrane spanning domains. Because the presenilin mutations account for the majority of cases of inherited early onset forms of AD, understanding the normal function of the presenilins and how mutations in these proteins lead to Alzheimer disease are central questions in Alzheimer's research. In terms of AD, two aspects of presinilin activity have received particular attention. First, mutant presenilin has been shown to alter the relative levels of the longer and potentially more pathogenic amyloid Abeta peptide variants (i.e., Abeta1-42/43). Second, mutant presenilin has been shown to promote apoptosis. With regard to the role of presenilins in apoptosis, there is evidence suggesting that a protein-protein interaction between the COOH-terminus of PS2 and as yet unidentified protein(s) is responsible for activation for apoptosis. This proposal focuses on identifying and characterizing protein(s) which interacts with the COOH- terminus of the presenilins, mediating their effects on apoptosis and, possibly, on altering the relative levels of the longer Abeta variants. The specific aims are as follows: 1) To identify and characterize proteins that interact with the COOH-terminus of the presenilins; 2) To study the role of interactor protein(s) in presenilin-mediated apoptosis; 3) To dissect the role of interactor protein(s) in presenilin-mediated increases in longer Abeta variants; and, 4) To elucidate the relationship between presinilin-mediated apoptosis and presenilin-mediated increases in longer Abeta variants.