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， 在阿尔茨海默氏症患者和老鼠的大脑中， 模型线粒体如何积极积累Aβ尚不清楚，因此代表了一个很大的知识缺口 在外地我们的目标是了解这个积累过程的第一步，通过研究详细的 底物/受体相互作用的分子机制。我们已经确定Aβ被线粒体蛋白输入机制中的非经典受体Tom 22识别。在本提案中，我们希望 执行两个相关但独立的具体目标，以达到这一目标。1）。我们将描述 （2）应用生物物理、生物化学和细胞生物学手段，详细研究Aβ与Tom 22受体的关系。我们期望 测定了Tom 22和Tom 22/Aβ复合物的三维原子结构。功能和结构 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肽的过程，从而提供新的模型来筛选 能够破坏特异性Tom 22/Aβ相互作用。因此，预计这一提案的结果将 在治疗AD中Aβ引起的线粒体功能障碍方面具有重要的积极作用。

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.