DEGRADATION OF THE TRANSMEMBRANE DOMAIN OF APP

描述（摘自摘要） 该提案的总体目标是阐明 周转的基本途径和基本机制， I型膜跨膜结构域（TMD）降解 内质网中的跨膜蛋白。因为伽马射线- 淀粉样前体蛋白（APP）TMD的分泌酶加工 对淀粉样蛋白A β肽的产生至关重要， 为了确定A β羧基末端的长度，申请人 特别感兴趣的是研究可能有助于 产生更多的病理相关的Abeta 42， 阿尔茨海默病（AD）。为了实现这些目标，他们 提出三个具体目标，探索战区导弹防御系统的基本机制 蛋白质水解和降解，检查它们与γ 分泌酶加工和定义有助于Abeta的途径 生产在第一个具体目标中，他们将开发一种新的探针， 他们专门设计用来检测 膜。申请人提出了五个次级目标，旨在增加 我们对这些疾病的基本机制和途径的理解， 膜蛋白TMD的降解和周转， 研究这些途径如何促进γ分泌酶 处理.有两种可能的方式，其中TMD的退化和 γ分泌酶处理可能与TMD降解有关， 通过破坏错误折叠的APP底物产生淀粉样蛋白， 否则会产生Abeta， 病理性β 1 -42淀粉样蛋白。或者，降解剂 途径可能会引起Abeta作为部分或不完全的结果， 降解在第二个具体目标中，他们将分析 位点2蛋白酶（S2 P）在TMD周转和APP加工中的作用。这 蛋白酶最近已被鉴定为切割 跨膜结构域内的甾醇反应元件结合蛋白 初步数据显示，缺乏这种活性的细胞也 TMD探针的周转率不足。第三个具体目标是 表征APP加工和Abeta产生的途径， 一种独特的细胞系，主要分泌（总Abeta的80%） 淀粉样蛋白的病理性A β 1 -42型。确定和 表征优先产生的途径 Abeta 1 -42可能为淀粉样蛋白的病理途径提供见解 阿尔茨海默氏症的发病机制。

DESCRIPTION (from abstract) The overall goals of the proposal are to elucidate some of the fundamental pathways and basic mechanisms for the turnover and degradation of the transmembrane domains (TMD) of type I membrane spanning proteins in the endoplasmic reticulum. Because the gamma- secretase processing of the TMD of the amyloid precursor protein (APP) is critical for the production of the amyloid Abeta peptide and determining the length of the carboxyl terminus of Abeta, the applicants are especially interested in examining pathways that may contribute to the production of the more pathologically relevant Abeta42 in Alzheimer's disease (AD). In order to accomplish these goals, they propose three specific aims that explore the basic mechanisms for TMD proteolysis and degradation, examine their relationship to gamma secretase processing and define the pathways that contribute to Abeta production. In the first specific aim, they will exploit a novel probe that they have designed to specifically examine cleavage events within the membrane. The applicants propose five sub-aims designed to increase our understanding of the basic mechanisms and pathways for the degradation and turnover of the TMD of membrane proteins and to investigate how these pathways may contribute to gamma secretase processing. There are two potential ways in which TMD degradation and gamma secretase processing may be linked: TMD degradation may prevent amyloid production by destroying mis-folded APP substrates that would otherwise give rise to Abeta and perhaps preferentially the more pathological Abeta1-42 form of amyloid. Alternatively, the degradative pathways may give rise to Abeta as a result of partial or incomplete degradation. In the second specific aim, they will analyze the potential role of site 2 protease (S2P) in TMD turnover and APP processing. This protease has recently been identified as the enzyme that cleaves the sterol response element binding protein within the transmembrane domain and preliminary data show that cells deficient in this activity are also deficient in the turnover of the TMD probe. The third specific aim is to characterize the pathways of APP processing and Abeta production in a unique cell line that secretes predominantly (80% of the total Abeta) the more pathological Abeta1-42 form of amyloid. The identification and characterization of the pathways that give rise preferentially to Abeta1-42 may provide insight into the pathological pathways of amyloid production in Alzheimer's disease.