Neuronal Mechanisms of Copper Transport and Toxicity

项目总结 阿尔茨海默病(AD)是一种使人衰弱的痴呆症，也是美国主要的死亡原因。 显性致病模型假设，启动因素要么是 阿尔茨海默病前体蛋白(APP)，导致淀粉样肽有毒物质在脑内积聚 或阿尔茨海默病相关等位基因APOE4的表达。在这些模型中，线粒体响应 与淀粉样多肽或APOE4的毒性有关，而不是线粒体驱动发病机制。在这里，我们探索一种 铜向线粒体输送机制中的遗传缺陷引发的线粒体新机制 (ATP7A，SLC31A1，COX17)，线粒体内膜柠檬酸转运蛋白SLC25A1和 它的相互作用蛋白NDUFS3。后者是一种与阿尔茨海默病的遗传风险基因相关的基因.我们 发现最终影响线粒体的这些基因突变下游的主要缺陷是 胆固醇合成途径、胆固醇和载脂蛋白E的表达上调。这些发现有 深刻的影响，因为他们认为胆固醇和载脂蛋白E的上调是阿尔茨海默氏症的关键风险因素 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一系列事件的末端环节 阿尔茨海默氏症。我们设想我们的线粒体驱动的致病模型是一个强大的补充，而不是 而不是取代目前由淀粉样肽或APOE4驱动的阿尔茨海默氏病的发病机制。我们 认为线粒体作为病理的始发者是一个重要的概念，因为它认为疾病 将在一个正前馈循环中解体，整合淀粉样多肽、APOE4、胆固醇和 线粒体。我们将用老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输送，并 建立了具有临床和遗传学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.