Impact of Somatic Mitochondrial DNA Point Mutations in the Aging Brain

体细胞线粒体 DNA 点突变对大脑衰老的影响

• 批准号: 8118522
• 负责人: DAVID K. SIMON
• 金额: $ 7.36万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8118522
• 关键词: Acceleration; Accounting; Age; Aging; Attention; Behavior; Behavioral; Brain; Cells; Cessation of life; Corpus striatum structure; Data; Dopamine; Elderly; Exposure to; Impairment; Incidence; Levodopa; Measures; Mitochondria; Mitochondrial DNA; Motor; Mus; Mutation; Neurodegenerative Disorders; Neurologic; Neurons; Parkinson Disease; Phenotype; Point Mutation; Polymerase; Predisposition; Premature aging syndrome; Publishing; Role; Series; Somatic Mutation; Substantia nigra structure; Testing; Toxin; Wild Type Mouse; age related; aging brain; base; brain cell; dopaminergic neuron; driving force; laser capture microdissection; mitochondrial DNA mutation; neuron loss; normal aging; public health relevance

DESCRIPTION (provided by applicant): A groundbreaking set of recent studies revealed that homozygous "mutator" mice expressing a proofreading deficient mitochondrial polymerase gamma (Polg ) accumulate both mtDNA point mutations and large deletions in association with a premature aging phenotype, demonstrating that somatic mitochondrial DNA (mtDNA) mutations can contribute to an aging phenotype. Large mtDNA deletions rather than point mutations have been proposed to be the driving force behind the aging phenotype, in part based on the lack of an overt phenotype in heterozygous mutator mice despite high levels of mtDNA point mutations and normal levels of deletions. However, we strongly argue in favor of the alternative hypothesis that mtDNA point mutations drive the aging phenotype in the mutator mice, an argument supported by our preliminary data, and propose to further test this hypothesis with particular attention to the neurological phenotype in the heterozygous mice. Several studies have demonstrated a normal age-related loss of dopaminergic substantia nigra (SN) neurons, as well as a marked enhancement with aging in the vulnerability of these neurons to mitochondrial toxins. However, studies of these or other age-related changes in the brain are lacking in the Polg mutator mice. Elucidating the cause of age-related vulnerabilities in the brain represents a critical step in advancing our understanding of normal aging in the brain and potentially of age-related neurodegenerative diseases such as Parkinson's disease (PD). We hypothesize that somatic mtDNA point mutations are a major cause of these age-related vulnerabilities of dopaminergic neurons, and therefore we predict that both heterozygous and homozygous Polg mutator mice will show increased spontaneous age related loss of dopaminergic neurons in addition to an enhanced susceptibility to toxin-induced degeneration of dopaminergic SN neurons compared to wild-type littermate controls. The proposed studies will directly test these predictions, and thus will help to clarify the important issue of the role of mtDNA point mutations in the aging brain. PUBLIC HEALTH RELEVANCE: set of cells in the brain that produce dopamine degenerate in Parkinson's disease. These same cells show a greatly enhanced vulnerability with advancing age to death from exposure to certain toxins, potentially accounting for the dramatic rise with age in the incidence of Parkinson's disease. We propose a series of studies to investigate the hypothesis that acquired mitochondrial DNA mutations account for the age-related vulnerability of these brain cells to degeneration.

描述（由申请人提供）：最近一系列开创性的研究表明，表达校对缺陷线粒体聚合酶 γ (Polg) 的纯合“突变”小鼠会积累与过早衰老表型相关的 mtDNA 点突变和大缺失，这表明体细胞线粒体DNA (mtDNA) 突变可能导致衰老表型。人们认为，较大的mtDNA缺失而不是点突变是衰老表型背后的驱动力，部分原因是杂合突变小鼠中尽管存在高水平的mtDNA点突变和正常水平的缺失，但缺乏明显的表型。然而，我们强烈支持另一种假设，即 mtDNA 点突变驱动突变小鼠的衰老表型，这一论点得到了我们初步数据的支持，并建议进一步检验这一假设，特别关注杂合小鼠的神经表型。多项研究表明，多巴胺能黑质 (SN) 神经元的正常损失与年龄相关，并且随着年龄的增长，这些神经元对线粒体毒素的脆弱性显着增强。然而，Polg 突变小鼠的大脑中缺乏这些或其他与年龄相关的变化的研究。阐明大脑中与年龄相关的脆弱性的原因是推进我们对大脑正常衰老以及帕金森病等与年龄相关的神经退行性疾病的潜在了解的关键一步。我们假设体细胞 mtDNA 点突变是多巴胺能神经元这些与年龄相关的脆弱性的主要原因，因此我们预测杂合子和纯合 Polg 突变小鼠除了对多巴胺能神经元的易感性增强之外，还会表现出与年龄相关的多巴胺能神经元的自发损失增加。与野生型同窝对照相比，毒素诱导的多巴胺能 SN 神经元变性。拟议的研究将直接检验这些预测，从而有助于阐明线粒体DNA点突变在大脑衰老中的作用这一重要问题。 公共卫生相关性：大脑中产生多巴胺的一组细胞在帕金森病中退化。随着年龄的增长，这些细胞表现出极大的脆弱性，甚至因接触某些毒素而死亡，这可能是帕金森病发病率随着年龄的增长而急剧上升的原因。我们提出了一系列研究来调查以下假设：获得性线粒体 DNA 突变解释了这些脑细胞与年龄相关的退化脆弱性。

项目成果

Significant changes in mitochondrial distribution in different pain models of mice.

不同疼痛模型小鼠线粒体分布的显着变化。

• 发表时间: 2013-07
• 影响因子: 4.4
• 作者: Guo, Bao;Sui, Bing;Wang, Xue;Wei, Yan;Huang, Jing;Chen, Jing;Wu, Sheng;Li, Yun;Wang, Ya;Yang, Yan
• 通讯作者: Yang, Yan

Somatic mitochondrial DNA mutations do not increase neuronal vulnerability to MPTP in young POLG mutator mice.

体细胞线粒体 DNA 突变不会增加年轻 POLG 突变小鼠神经元对 MPTP 的脆弱性。

• 发表时间: 2014-11
• 影响因子: 2.9
• 作者: Dai, Ying;Clark, Joanne;Zheng, Kangni;Kujoth, Gregory C;Prolla, Tomas A;Simon, David K
• 通讯作者: Simon, David K

Behavioral and metabolic characterization of heterozygous and homozygous POLG mutator mice.

杂合子和纯合 POLG 突变小鼠的行为和代谢特征。

• 发表时间: 2013-07
• 影响因子: 4.4
• 作者: Dai, Ying;Kiselak, Tomas;Clark, Joanne;Clore, Elizabeth;Zheng, Kangni;Cheng, Allen;Kujoth, Gregory C;Prolla, Tomas A;Maratos;Simon, David K
• 通讯作者: Simon, David K