Cellular and Molecular Consequences of Respiratory Chain Defects in Neurons

线粒体氧化磷酸化(OXPHOS)缺陷与多种原发疾病相关 线粒体疾病以及神经退行性疾病。这类疾病可能由以下缺陷引起 核或线粒体DNA(MtDNA)。我们建议利用现有的和新的鼠标模型 我们实验室创造了操纵线粒体DNA来研究线粒体DNA作用的基本机制 神经退行性变的突变。我们还将使用DNA编辑酶进一步调节mtDNA 体内的异质性。我们将分析不同类型神经元(谷氨酸能和多巴胺能)的能力 积累线粒体DNA缺失(目标1)和tRNA基因的致病点突变(目标2)。有了这些 模型建立后，我们还将研究谷氨酸能和多巴胺能神经元亚型对 氧磷酸盐缺陷。

Defects in mitochondrial oxidative phosphorylation (OXPHOS) have been associated with various primary mitochondrial diseases as well as with neurodegenerative disorders. Such disorders can be caused by defects in nuclear or mitochondrial DNA (mtDNA). We propose to take advantage of existing and new mouse models created in our lab to manipulate the mtDNA to study fundamental mechanisms of the role of mtDNA mutations in neurodegeneration. We will also use DNA editing enzymes to further modulate mtDNA heteroplasmy in vivo. We will analyze the ability of different neuronal types (glutamatergic and dopaminergic) to accumulate mtDNA deletions (aim#1) and a pathogenic point mutation in a tRNA gene (aim#2). With these models in place, we will also study the susceptibility of glutamatergic and dopaminergic neuronal subtypes to OXPHOS defects.