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

正常和阿尔茨海默脑中与年龄相关的体细胞突变的速率和机制

• 批准号: 10376742
• 负责人: Eunjung Alice Lee
• 金额: $ 86.6万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10376742
• 关键词: Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Area; Astrocytes; Autopsy; Birth; Brain; Brain Diseases; Brain Neoplasms; Brain region; Cell division; Cells; Cognitive aging; DNA; DNA sequencing; Data; Disease; Elderly; Event; Freezing; Genome; Glioma; Goals; Health; Hippocampus (Brain); Human; Individual; Life; Methods; Microglia; Molecular; Motor Cortex; Mutation; Neonatal; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neuronal Dysfunction; Neurons; Oligodendroglia; Pathologic Mutagenesis; Pattern; Persons; Prefrontal Cortex; Process; Research; Single Nucleotide Polymorphism; Somatic Mutation; Techniques; Testing; Time; Variant; Work; age related; aged; brain cell; caudate nucleus; cell type; dentate gyrus; design; disorder risk; entorhinal cortex; genome sequencing; genome-wide; genome-wide analysis; genotoxicity; human old age (65+); insight; mind control; neuronal metabolism; normal aging; oxidative damage; stem cells; tau Proteins; tau-1; technological innovation; therapy development; tool; whole genome

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.

人类的衰老与许多脑部疾病有关，包括神经胶质祖细胞肿瘤 和神经元细胞的变性。然而，年龄和疾病风险相互作用的机制是 不太了解。我们小组最近的研究表明，体细胞单核苷酸变异（sSNV） 甚至在人类皮层的非分裂神经元中积累，导致每个神经元中有数千个sSNV 基因组。此外，发现的sSNV模式可以分类，正常的大脑出现 有出生时就存在的体细胞变异，随着时间的推移积累的变异，以及由 氧化损伤我们的研究还发现，在神经元中sSNV积累的速率显著更高， 阿尔茨海默病（AD）大脑，可能与氧化损伤增加有关。这些研究依赖于新的 技术允许对从冷冻的单个神经元中分离的DNA进行深度全基因组测序 死后的大脑 这项新的研究旨在进一步描述在哺乳动物中积累的体细胞变异的速率和模式。 单个神经元和神经胶质作为一个个体的年龄，并确定如何这种突变的积累是相关的， AD以及神经胶质瘤的形成。第一个目标是检查正常大脑不同区域的神经元。 不同年龄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起作用的特定突变力量。第二个目标将执行类似的 分析，这一次集中在神经胶质细胞而不是神经元。在最后的目标，我们将看看神经元在 AD患者的大脑，并分析与老年人相比， 匹配正常大脑这将为AD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，个体神经元中的体细胞突变是一个重要的 至少在一些神经退行性疾病中，我们的数据表明它们与正常的认知老化有关。 这是第一次，工具存在，以检查这些问题，这项研究的目的是确定如何 体细胞SNV影响正常衰老、脑肿瘤形成和AD。这是理解 AD的分子原因，以及治疗和治愈的发展的先决条件。