Mitochondrial Amyloid Beta accumulation via non-canonical receptor Tom22

令人信服的证据表明线粒体功能障碍是阿尔茨海默病的早期事件 (Ad)病理生理学。这种线粒体功能障碍与细胞内Aβ水平升高密切相关， 它似乎积聚在阿尔茨海默氏症患者和小鼠大脑中的线粒体中 模特们。线粒体如何主动积累Aβ尚不清楚，因此代表着知识的巨大缺口 在战场上。我们的目标是通过研究细节来理解这个积累过程的第一步 底物/受体相互作用的分子机制。我们已经确定Aβ是由线粒体蛋白质输入机制中的一个非典范受体Tom22识别的。在这项提案中，我们希望 执行两个相互关联但又相互独立的具体目标来实现这一目标。1)。我们将描述交互作用的特征 通过生物物理、生化和细胞生物学手段，详细研究Aβ和Tom22受体之间的相互作用；我们希望 测定了Tom22和Tom22/Aβ络合物的三维原子结构。功能和结构 在这里获得的信息有望揭示详细的分子机制，强调有害的 线粒体摄取Aβ多肽的过程，从而为筛选 能够中断特定的Tom22/Aβ相互作用。因此，预计这项提案的结果将是 对治疗Aβ所致的AD线粒体功能障碍有重要的积极作用。

Compelling evidence has suggested that mitochondrial dysfunction is an early event in Alzheimer’s Disease (AD) pathophysiology. This mitochondrial dysfunction is closely related to the elevated level of intracellular Aβ, which appears to be accumulated within mitochondria in the brains of both Alzheimer’s patients and mouse models. How mitochondria actively accumulate Aβ is not clear, and thus represents a large gap of knowledge in the field. We aim to understand the very first step of this accumulation process by studying the detailed molecular mechanism of substrate/receptor interaction. We have identified that Aβ is recognized by a non-canonical receptor, Tom22, within the mitochondrial protein import machinery. In this proposal, we expect to perform two related but independent specific aims to reach that goal. 1). We will characterize the interaction between Aβ and Tom22 receptor in details, by biophysical, biochemical and cell biology tools; 2). We expect to determine three dimensional atomic structures of Tom22 and Tom22/Aβ complex. The functional and structural information gained here are expected to reveal detailed molecular mechanism underlining the detrimental process of mitochondrial uptake of Aβ peptides, and thus provide novel models to screen molecules that are capable of disrupting the specific Tom22/Aβ interaction. Thus, the outcome of this proposal is expected to have important positive impact in treating mitochondrial dysfunction caused by Aβ in AD.