Impact of Somatic Mitochondrial DNA Point Mutations in the Aging Brain

描述（由申请人提供）：最近的一组突破性研究表明，表达校对缺陷线粒体聚合酶γ (Polg)的纯合“突变”小鼠积累与早衰表型相关的mtDNA点突变和大缺失，表明体细胞线粒体DNA （mtDNA）突变可以促进衰老表型。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，部分原因是杂合突变小鼠尽管存在高水平的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的初步数据的支持，并建议进一步验证这一假设，特别关注杂合小鼠的神经表型。一些研究表明，多巴胺能黑质（SN）神经元的正常年龄相关损失，以及随着年龄的增长，这些神经元对线粒体毒素的易感性显著增强。然而，对这些或其他与年龄相关的大脑变化的研究在Polg突变小鼠中缺乏。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与年龄相关的神经退行性疾病（如帕金森病）的潜在理解的关键一步。我们假设体细胞mtDNA点突变是这些多巴胺能神经元年龄相关脆弱性的主要原因，因此我们预测杂合和纯合polymutator小鼠与野生型对照相比，会表现出更多的多巴胺能神经元自发性年龄相关损失，以及对毒素诱导的多巴胺能SN神经元变性的易感性增强。拟议的研究将直接测试这些预测，因此将有助于澄清mtDNA点突变在衰老大脑中的作用这一重要问题。

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.