Recessive parkinsonism and mitochondrial function

隐性帕金森症和线粒体功能

• 批准号: 9351988
• 负责人: Mark Cookson
• 金额: $ 18.25万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9351988
• 关键词: 1-Methyl-4-phenylpyridinium; Aging; Animals; Cell Culture Techniques; Cell Death; Complex; Data; Inherited; Investigation; Mitochondria; Modeling; Mutation; Neurons; Parkinsonian Disorders; Phenotype; Polymerase; Reporting; Rotenone; Series; Techniques; Work; age related; dopaminergic neuron; enzyme activity; in vitro Model; in vivo; inhibitor/antagonist; interest; mitochondrial DNA mutation; mitochondrial dysfunction; mutant; neuron loss; neuronal survival; research study

We have been working on how mitochondrial function influences neuronal survival, particularly in the context of inherited forms of parkinsonism. To this end, we have been examining accelerated aging models including one with a mutation in the mitochondrial polymerase gamma that diminishes proofreading activity of the enzyme, leading to accumulation of mitochondrial DNA mutations. We previously reported that, using a series of high content techniques, PolG mutant animals had loss of mitochondrial complex I assembly. Given that previous data from cell culture experiments suggested that DJ-1 deficiency was associated with an increased sensitivity to complex I inhibitors such as rotenone or MPP+, we therefore expected that crossing PolG and DJ-1 animals would result in loss of dopaminergic phenotypes. However, despite extensive investigation in appropriately powered studies we did not find any evidence of neuronal loss in the double mutants.

我们一直在研究线粒体功能如何影响神经元的存活，特别是在遗传性帕金森病的背景下。为此，我们一直在研究加速衰老的模型，包括线粒体聚合酶伽马突变，该突变会降低酶的校对活性，导致线粒体DNA突变的积累。我们此前报道，使用一系列高含量技术，Polg突变动物失去了线粒体复合体I组装。鉴于以前的细胞培养实验数据表明，DJ-1缺乏与对鱼藤酮或MPP+等复杂I抑制剂的敏感性增加有关，因此我们预计与Polg和DJ-1杂交将导致多巴胺能表型的丧失。然而，尽管我们在适当的研究中进行了广泛的调查，但我们没有发现任何证据表明双重突变体中有神经元丢失。