Neuronal Mechanisms of Copper Transport and Toxicity

项目摘要 阿尔茨海默病（AD）是一种使人衰弱的痴呆形式，并且是美国的主要死亡原因。 显性发病机制模型假定起始因素是细胞的异常加工， 阿尔茨海默氏症前体蛋白（APP），其导致淀粉样肽毒性物质在脑中的积累 或阿尔茨海默病相关等位基因APOE4的表达。在这些模型中， 淀粉样肽或APOE4的毒性，而不是线粒体驱动的发病机制。在这里，我们探索一个 一种新的线粒体机制，由线粒体铜传递机制的遗传缺陷引发 （ATP 7A、SLC 31 A1、C0X 17）、线粒体内膜线粒体柠檬酸转运蛋白SLC 25 A1和 其相互作用蛋白NDUFS3。后者是与阿尔茨海默病的遗传风险位点相关的基因。我们 发现这些最终影响线粒体的基因突变下游的主要缺陷是 胆固醇合成途径、胆固醇和APOE表达的上调。这些发现 这意味着阿尔茨海默氏症的关键风险因素胆固醇和载脂蛋白E的上调 疾病是由影响线粒体的遗传缺陷引起的。我们的模型挑战了当前的规范 认为线粒体功能障碍是导致突触功能障碍的事件链的末端环节， 老年痴呆症我们设想我们的神经元驱动的发病机制模型作为一个强大的补充，而不是 而不是替代目前淀粉样肽或APOE4驱动的阿尔茨海默病发病机制的范例。我们 他认为，作为病理学的发起者，神经元是一个重要的概念，因为它认为疾病 将在一个整合淀粉样肽、APOE 4、胆固醇和 线粒体我们将用小鼠突变体来验证这一假设，这些突变体会损害铜向线粒体的转运， 建立了具有临床和遗传有效性的阿尔茨海默病动物模型。

PROJECT SUMMARY Alzheimer’s disease (AD) is a debilitating form of dementia, and a leading cause of death in the United States. Dominant pathogenesis models postulate that initiating factor are either the aberrant processing of the Alzheimer’s precursor protein (APP), which leads to the accumulation of amyloid peptide toxic species in brain or the expression of an Alzheimer’s disease associated allele, APOE4. In these models, mitochondria respond to the toxicity of amyloid peptides or APOE4 rather than mitochondria driving pathogenesis. Here we explore a novel mitochondrial mechanism initiated by genetic defects in copper delivery mechanisms to the mitochondria (ATP7A, SLC31A1, COX17), the inner mitochondrial membrane mitochondrial citrate transporter SLC25A1 and its interacting protein, NDUFS3. The latter a gene associated to a genetic risk loci in Alzheimer’s disease. We found that the main defect downstream of mutations in these genes that end affecting mitochondria is an upregulation of cholesterol synthesis pathways, cholesterol, and the expression of APOE. These findings have profound implications as they suggest that upregulation of cholesterol and APOE, key risks factor for Alzheimer’s disease, are initiated by a genetic defect affecting mitochondria. Our model challenges the current canonical view that mitochondrial dysfunction is a terminal link in a chain of events ending in synapse dysfunction and Alzheimer’s disease. We envision our mitochondria-driven pathogenesis model as a powerful addition rather than a replacement of the current paradigm of amyloid peptide- or APOE4-driven Alzheimer’s pathogenesis. We posit that the mitochondrion acting as initiator of pathology is an important concept because it argues that disease would unravel in a positive feed-forward circle integrating amyloid peptides, APOE4, cholesterol, and mitochondria. We will test this hypothesis with mouse mutants that impair copper delivery to mitochondria and stablished animal models of Alzheimer’s disease with clinical and genetic validity.