Impact of Somatic Mitochondrial DNA Point Mutations in the Aging Brain

描述(申请人提供)：一组突破性的最新研究显示，表达校对缺陷线粒体聚合酶伽马(Polg)的纯合“突变”小鼠会积累与过早衰老表型相关的mtDNA点突变和大片段缺失，表明体细胞线粒体DNA(MtDNA)突变可导致衰老表型。大的mtDNA缺失而不是点突变被认为是衰老表型背后的驱动力，部分原因是尽管mtDNA点突变水平高，缺失水平正常，但杂合子突变小鼠缺乏明显的表型。然而，我们强烈支持另一种假说，即mtDNA点突变导致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，并建议进一步测试这一假说，特别关注杂合子小鼠的神经表型。一些研究表明，多巴胺能黑质(SN)神经元存在正常的与年龄相关的丢失，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著增强。然而，在Polg突变小鼠中，缺乏关于这些或其他与年龄相关的大脑变化的研究。阐明大脑中与年龄相关的脆弱性的原因是促进我们对大脑正常衰老以及潜在的与年龄相关的神经退行性疾病(如帕金森氏病)的理解的关键一步。我们假设体细胞mtDNA点突变是这些与年龄相关的多巴胺能神经元脆弱性的主要原因，因此我们预测杂合和纯合子Polg突变小鼠将表现出与年龄相关的自发多巴胺能神经元丢失增加，此外，与野生型斜发对照相比，对毒素诱导的多巴胺能神经元变性的易感性增强。这项拟议的研究将直接检验这些预测，从而有助于澄清线粒体DNA点突变在衰老大脑中的作用这一重要问题。 与公共健康相关：帕金森氏症患者大脑中一组产生多巴胺的细胞退化。这些细胞随着年龄的增长而显示出极大的脆弱性，这些细胞因接触某些毒素而死亡，这可能是帕金森氏症发病率随年龄急剧上升的原因。我们提出了一系列研究来调查这一假说，即获得性线粒体DNA突变是这些脑细胞与年龄相关的退化脆弱性的原因。

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.