Mitochondria and metabolism in neurodegeneration

摘要 目前，约有580万美国人患有阿尔茨海默病(AD)1，目前仍未获得批准 减少相关神经元功能障碍和细胞死亡的治疗方法。各种针对AD的临床试验 “淀粉样蛋白级联”被证明是不成功的，这表明迫切需要重新考虑AD疾病的进展。 据报道，细胞内钙离子和线粒体功能的改变是关键的分子因素 对AD发病机制的影响。我们的实验室以前已经证明，对mCa~(2+)摄取或外流的遗传调节是 在细胞应激背景下限制线粒体功能障碍和细胞死亡的有效方法 [Ca2+]i。作为阿尔茨海默病患者线粒体钙交换受损的因果证据，我们建立了多个突变的小鼠模型 调节神经元NCLX的表达，这是可兴奋细胞中2+外流的主要机制，以及 MCA 发现线粒体钙外流受损导致3xTg-1神经病理和记忆能力下降 广告鼠标模型。除了在 MCA 2+外流，我们还发现了显著的蛋白质组重构 线粒体钙单转运体通道(MTCU)。MTCU是急性钙摄取进入细胞所必需的 线粒体基质，在那里它调节线粒体功能。MTCU是一个多蛋白通道，包括 包括造孔剂、支架和调节元件。到目前为止，还没有发表的体内研究使用 定义线粒体钙摄取与阿尔茨海默病进展的关系的遗传模型 关于钙离子外流在阿尔茨海默病发病中的作用的研究结果17，我们迫切需要从机械上定义 在进行治疗开发之前，mCa~(2+)摄取途径。在这个项目中，我们假设 线粒体钙超载是AD病理的主要因素，它通过促进代谢功能障碍和 神经细胞死亡，减少MTCU依赖的mCa+摄取将阻止神经退变 和AD的发病机制。此外，使用复杂的突变小鼠模型，我们将系统地定义 阿尔茨海默病进展相关的线粒体代谢和蛋白质组学变化及线粒体钙离子变化 流量。最好的情况是，这些研究将确定AD治疗的新治疗靶点。

SUMMARY Currently, ~5.8 million Americans suffer from Alzheimer's disease (AD)1 and there remain no approved therapeutics to lessen the associated neuronal dysfunction and cell death. Various AD clinical trials targeting the “amyloid cascade” have proven unsuccessful, suggesting a dire need to rethink AD disease progression. Alterations in cellular calcium (iCa2+) and mitochondrial function are reported as critical molecular contributors to AD pathogenesis. Our lab has previously shown that genetic modulation of either mCa2+ uptake or efflux is a powerful way to limit mitochondrial dysfunction and cell death in the context of cell stress featuring elevated iCa2+. As causal evidence of impaired mCa2+ exchange in AD, we generated multiple mutant mouse models to modulate neuronal NCLX expression, the primary mechanism for 2+ efflux in excitable cells, and mCa discovered that impaired mitochondrial calcium efflux proceeds neuropathology and memory decline in 3xTg- AD mouse model. In addition to alterations in mCa 2+ efflux, we also discovered significant proteomic remodeling of the mitochondrial calcium uniporter channel (mtCU). The mtCU is required for acute Ca2+ uptake into the mitochondrial matrix where it regulates mitochondrial function. The mtCU is a multiprotein channel, consisting of pore-forming, scaffold, and regulatory components. To date, there are no published in vivo studies using genetic models to define the contribution of mCa2+ uptake with AD disease progression and given our published findings regarding the role of mCa2+ efflux in AD pathogenesis17, it's imperative that we mechanistically define the mCa2+ uptake pathway prior to proceeding with therapeutic development. In this project, we hypothesize that mCa2+overload is a primary contributor to AD pathology by promoting metabolic dysfunction and neuronal cell death, and that reducing mtCU-dependent mCa2+ uptake will impede neurodegeneration and AD pathogenesis. Further, using complex mutant mouse models we will systematically define the mitochondrial metabolomic and proteomic changes associated with AD progression and alterations in mCa2+ flux. Optimally, these studies will identify new therapeutic targets for the treatment of AD.