Mechanisms underlying DNA double strand break response in Alzheimer?s disease and frontal temporal dementia

DNA损伤扰乱了基因组的稳定性，并与年龄相关的认知能力下降有关，也与 各种神经退行性疾病的早期阶段，包括阿尔茨海默病(AD)、肌营养不良侧索 硬化症和额颞痴呆(FTD)。然而，我们对DNA损伤机制的理解 导致神经元脆弱性和退化仍然是一个悬而未决但极其重要的问题 问题。一个主要的混淆因素是与最相关的损害来源 神经退行性变仍然未知，将基因组不稳定与 人们对神经退行性变知之甚少。此外，尚不清楚大脑功能是否恶化 仅仅是由于DNA损伤在整个基因组中的随机积累，或者是否存在 在这一过程中起到中介作用的损害“热点”。我们研究的目标是更好地理解 神经退行性变中基因组不稳定性的潜在机制和寻找新的治疗靶点 抑制这一神经元脆弱性的早期病理特征。我们假设基因组不稳定性是一种 AD和FTD认知功能减退和神经元易损性的主要潜在机制。走向测试 在这一假设下，我们的具体目标是：1)识别容易积累的基因组座位 小鼠和人诱导的多能细胞DNA损伤，特别是DNA双链断裂(DSB) (IPSC)衍生的AD和FTD模型，2)确定DSB信号/修复的准确缺陷 和人类IPSC衍生的AD和FTD模型，以及3)识别减少DNA损伤的修饰物 用一种新的高通量方法检测家族性AD和FTD患者IPSC来源的神经细胞的敏感性 筛选策略。我们的初步研究结果表明，DNA双链断裂过多是一种早期病理现象。 神经退行性变的标志，可以在老鼠和人类系统中建模。获得更多 神经退行性变背景下对DNA双链断裂反应和/或修复失败的机械论洞察 突变将扩大我们对基因组不稳定如何导致大脑健康和 并为神经变性的早期治疗干预提供了新的途径。

DNA damage perturbs genomic stability and has been linked to age-associated cognitive decline, as well as to early stages of various neurodegenerative disorders including Alzheimer’s disease (AD), amyotrophic lateral sclerosis, and frontotemporal dementia (FTD). However, our mechanistic understanding of how DNA damage contributes to neuronal vulnerability and deterioration remains an unresolved, yet extremely important question. A major confounding factor is that the sources of damage that are most pertinent to neurodegeneration remain unknown and the precise mechanisms that connect genomic instability to neurodegeneration are poorly understood. In addition, it is unclear whether the deterioration of brain function results solely from a random accumulation of DNA damage throughout the genome, or whether there are “hotspots” of damage that mediate this process. The goal of our research is to better understand the mechanisms underlying genomic instability in neurodegeneration and identify novel therapeutic targets to dampen this early pathological hallmark of neuronal vulnerability. We hypothesize that genomic instability is a major underlying mechanism of cognitive decline and neuronal vulnerability in AD and FTD. Towards testing this hypothesis, our specific aims are: 1) to identify genomic loci that are vulnerable to the accumulation of DNA damage, particularly DNA double strand breaks (DSBs) in mouse and human induced pluripotent cell (iPSC)-derived models of AD and FTD, 2) to determine the precise defects in DSB signaling/repair in mouse and human iPSC-derived models of AD and FTD, and 3) to identify modifiers that reduce DNA damage susceptibility in iPSC-derived neural cells from patients with familial AD and FTD using a novel high-throughput screening strategy. Our preliminary findings suggest that excessive DNA DSBs are an early pathological hallmark of neurodegeneration that can be modeled in both mouse and human systems. Obtaining increased mechanistic insight into the failure to respond to and/or repair DNA DSBs in the context of neurodegenerative mutations will broaden our understanding of how genomic instability contributes to decline in brain health and cognition, and provide novel avenues for early therapeutic intervention in neurodegeneration.