Rates and mechanisms of age-related somatic mutation in normal and Alzheimer brain

人类的衰老与许多脑部疾病有关，包括神经胶质前体细胞肿瘤。 神经细胞变性。然而，年龄和疾病风险相互作用的机制是 人们对此知之甚少。本课题组最近的研究表明，体细胞单核苷酸变异(SSNV) 即使在人类大脑皮层未分裂的神经元中也会积累，导致每个神经元产生数千个sSNV 到老年时的基因组。此外，可以对发现的sSNV模式进行分类，并出现正常的大脑 拥有出生时就存在的体细胞变异，随着时间的推移积累起来的变异，以及由 氧化损伤。我们的研究还发现，在神经细胞中， 阿尔茨海默病(AD)的大脑，可能与氧化损伤增加有关。这些研究依赖于新的 对从冰冻的单个神经元中分离的DNA进行深度全基因组测序的技术 死后大脑。 这项新的研究旨在进一步表征在体内积累的体细胞变异的比率和模式 单个神经元和胶质细胞随着个体的衰老，并确定这种突变的积累是如何与 AD以及神经胶质瘤的形成。第一个目标是检查正常脑区不同区域的神经元。 不同年龄段的大脑。这将使我们更好地了解这些突变是如何随着年龄的增长而积累的， 以及在不同大脑区域发挥作用的特定突变力量。第二个目标将执行类似的 分析，这一次的重点是神经胶质细胞，而不是神经元。在最终目标中，我们将观察大脑中 阿尔茨海默病患者的大脑，并分析与老年人相比，突变的速度和模式有何不同- 与正常大脑相匹配。这将为AD的体细胞突变的原因提供有价值的见解。 有令人信服的证据表明，个体神经元的体细胞突变是一个重要的 至少是一些神经退行性疾病的因素，我们的数据表明它们与正常的认知老化有关。 这是第一次存在检查这些问题的工具，而这项研究旨在确定如何 躯体SNV影响正常衰老、脑肿瘤形成和AD。这是理解 阿尔茨海默病的分子病因，是发展治疗和治疗的先决条件。

Aging in humans is associated with a host of brain diseases, including tumors of glial progenitor cells and degeneration of neuronal cells. However, the mechanisms by which age and disease risk interact are poorly understood. Recent studies from our group have shown that somatic single nucleotide variants (sSNV) accumulate even in nondividing neurons in the human cortex, resulting in thousands of sSNV per neuronal genome by old age. Further, the patterns of sSNV that are found can be classified, and normal brains appear to have somatic variants that were present at birth, variants that accumulate over time, and variants caused by oxidative damage. Our studies also find a significantly higher rate of sSNV accumulation in neurons from Alzheimer’s disease (AD) brain, likely related to increased oxidative damage. These studies relied on new techniques that allow deep whole genome sequencing of DNA isolated from a single neuron taken from frozen postmortem brain. This new study aims to further characterize the rates and patters of somatic variants that accumulate in single neurons and glia as an individual ages, and determine how this accumulation of mutations is related to AD as well as the formation of glial tumors. The first aim will examine neurons form different regions of normal brain at different ages. This will give us a better understanding of how these mutations accumulate with age, and the specific mutational forces at work in different brain areas. The second aim will perform a similar analysis, this time focused on glial cells instead of neurons. In the final aim, we will look at neurons in the brains of individuals who had AD, and analyze how the rate and patter of mutations differ compared to aged- matched normal brain. This will provide valuable insight into the causes of somatic mutations in AD. There is compelling evidence to suggest that somatic mutations in individual neurons are an important factor in at least some neurodegenerative disorders, and our data implicate them in normal cognitive aging. For the first time, the tools exist to examine these questions, and this study is designed to determine how somatic SNV impact normal aging, brain tumor formation, and AD. This is a crucial step in understanding the molecular cause of AD, and a prerequisite to the development of treatments and cures.