Cellular and Molecular Consequences of Respiratory Chain Defects in Neurons

线粒体氧化磷酸化（OXPHOS）缺陷与各种原发性 线粒体疾病以及神经退行性疾病。这种疾病可能是由以下缺陷引起的： 核或线粒体DNA（mtDNA）。我们建议利用现有的和新的小鼠模型 在我们的实验室创建的操作线粒体DNA，研究线粒体DNA的作用的基本机制， 神经变性的突变我们还将使用DNA编辑酶来进一步调节mtDNA 体内异质性我们将分析不同类型的神经元（多巴胺能和多巴胺能） 积累mtDNA缺失（aim#1）和tRNA基因中的致病性点突变（aim#2）。与这些 在适当的模型中，我们还将研究多巴胺能和多巴胺能神经元亚型对 OXPHOS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.