Mitochondria and metabolism in neurodegeneration

神经退行性变中的线粒体和代谢

基本信息

批准号：
10183972
负责人：
John William Elrod
金额：
$ 227.05万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10183972
关键词：
3xTg-AD mouse Acute Adult Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology American Amyloid Biochemical Brain Calcium Cell Death Cell Death Signaling Process Cells Cellular Stress Clinical Trials Complex Coupled Development Diagnosis Disease Disease Progression Gatekeeping Genetic Genetic Models Goals Hippocampus (Brain)Impaired cognition Impairment Knock-in Mouse Knock-out Link Mediating Memory Loss Metabolic Metabolic dysfunction Metabolism Mitochondria Mitochondrial Matrix Modeling Molecular Mus Mutant Strains Mice Nerve Degeneration Neurofibrillary Tangles Neuronal Dysfunction Neurons Pathogenesis Pathology Pathway interactions Patients Phenotype Population Proteome Proteomics Publishing Reactive Oxygen Species Reporting Role Sampling Senile Plaques Severity of illness Stress System Testing Therapeutic Time age related calcium uniporter cognitive function defined contribution hyperphosphorylated tau in vivo loss of function metabolome metabolomics mitochondrial dysfunction mitochondrial metabolism mouse model mutant mouse model neuron loss neuropathology new therapeutic target scaffold theories therapeutic development uptake

项目摘要

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.

概括目前，约有580万美国人患有阿尔茨海默氏病（AD）1，尚无批准治疗剂可减少相关的神经元功能障碍和细胞死亡。各种广告临床试验针对事实证明，“淀粉样蛋白级联”未能成功，这表明需要重新考虑AD疾病进展。细胞钙（ICA2+）和线粒体功能的改变是关键分子贡献者进行AD发病机理。我们的实验室先前已经表明，MCA2+摄取或外排的遗传调节是一个在细胞应力升高的情况下，限制线粒体功能障碍和细胞死亡的强大方法 ICA2+。作为AD中MCA2+交换受损的因果证据，我们生成了多个突变小鼠模型调节神经元NCLX表达，这是令人兴奋细胞中2+外排的主要机制， MCA 发现线粒体钙外排受损会导致3xTG-的神经病理学和记忆下降 AD鼠标模型。除了改变 MCA 2+外排，我们还发现了明显的蛋白质组学重塑线粒体钙UNITER通道（MTCU）的MTCU是急性Ca2+摄取需要的线粒体基质调节线粒体功能。 MTCU是一个多蛋白通道，组成孔形成，脚手架和调节成分的组成部分。迄今为止，还没有使用使用的体内研究定义MCA2+摄取对AD疾病进展的贡献的遗传模型，并鉴于我们已发表的关于MCA2+外排在AD发病机理中的作用的发现17，我们必须机械定义在进行热发育之前，MCA2+摄取途径。在这个项目中，我们假设 MCA2+超载是通过促进代谢功能障碍和神经元细胞死亡以及减少MTCU依赖性MCA2+摄取将阻碍神经变性和AD发病机理。此外，使用复杂的突变鼠模型，我们将系统地定义线粒体代谢组学和蛋白质组学变化与AD进展和MCA2+的变化有关通量。最佳地，这些研究将确定用于治疗AD的新治疗靶标。