A Forgotten Connection: Retrotransposon contribution to Alzheimer's Disease

被遗忘的联系：逆转录转座子对阿尔茨海默病的贡献

• 批准号: 10288552
• 负责人: Victoria Perepelitsa Belancio
• 金额: $ 37.48万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-18 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10288552
• 关键词: Administrative Supplement; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Area; Brain; Case-Control Studies; Cerebral cortex; DNA; DNA Damage; Dementia; Detection; Development; Etiology; Funding; Genetic; Genetic Transcription; Genome; Genomics; Goals; Hippocampus (Brain); Impaired cognition; Individual; Legal patent; Mediating; Methods; Molecular; Neurofibrillary Tangles; Neurons; Outcome; Play; Prognostic Marker; Proteins; Research; Retrotransposition; Retrotransposon; Risk; Role; Testing; age related; epigenetic silencing; human DNA; improved; neuron loss; pre-clinical; promoter; therapy development

One goal of the existing R01 is the development of a high throughput method, called SCORE, for detection of polymorphic L1s (pL1s) retrotransposons in human DNA. Our existing R01 does not include any studies involving analysis of Alzheimer's Disease (AD) patents' genomes. However, such analysis would be within the scope of this R01 because pL1s and their DNA damage are a common theme of both the funded R01 and the proposed Administrative Supplement. The proposed research is important to AD because brains of AD patients have increased levels of DNA breaks compared to age-matched controls with evidence supporting that this damage leads to neuronal loss at the pre-clinical stage of AD when plaques and tangles have not yet been formed. Thus, identification of an additional mechanism(s) underlying neuronal loss will significantly improve our understanding of AD etiology and progress in treatment development. Several molecular mechanisms guard against L1-associated damage. One of them is a TRIM28-mediated suppression of L1 expression by epigenetic silencing of L1 promoters. Although TRIM28 is expressed in neurons throughout the brain, L1 damage occurs in hippocampus and cerebral cortex, which are the areas that are also affected in AD patients. Our preliminary findings show that, independent of its role in suppression of L1 transcription, TRIM28 interacts with L1 proteins and stimulates L1 retrotransposition. We hypothesize that genomes of AD patients have more pL1s than genomes of normal subjects, which can contribute to the neuronal loss associated with an increase in L1-associated DNA damage, especially when combined with deregulation of TRIM28. We will test our hypothesis through two specific aims. Aim 1 will perform a case-control study to determine the number of pL1s in the genomes of AD patients (case) and age-matched subjects without cognitive impairment (control). This aim will determine whether the number and/or composition of pL1s is associated with AD. Aim 2 will determine the mechanism of TRIM28 interaction with L1 ORF2p protein and its effect on L1 integration and DSB-formation. This aim will determine whether TRIM28 plays a dual role in the L1 amplification cycle and the mechanism of TRIM28-associated stimulation of L1 retrotransposition. Combined positive outcomes of these aims would justify large-scale studies testing the utility of genomic L1 content in identifying individual risk of developing AD and/or other age-related dementias.

现有 R01 的一个目标是开发一种高通量方法，称为 SCORE，用于检测人类 DNA 中的多态性 L1s (pL1s) 逆转录转座子。我们现有的 R01 不包括任何涉及阿尔茨海默病 (AD) 专利分析的研究 基因组。然而，此类分析属于本 R01 的范围，因为 pL1 及其 DNA 损伤是资助的 R01 和拟议的行政管理的共同主题 补充。这项研究对 AD 很重要，因为 AD 患者的大脑有 与年龄匹配的对照组相比，DNA 断裂水平增加，有证据表明 这种损害会导致 AD 临床前阶段的神经元损失，此时斑块和缠结已形成 尚未形成。因此，识别神经元损失的附加机制 将显着提高我们对 AD 病因和治疗进展的了解 发展。多种分子机制可防止 L1 相关损伤。其中之一 是 TRIM28 通过 L1 启动子表观遗传沉默介导的 L1 表达抑制。 尽管 TRIM28 在整个大脑的神经元中表达，但 L1 损伤发生在 海马体和大脑皮层，这些区域在 AD 患者中也受到影响。我们的 初步研究结果表明，无论 TRIM28 在 L1 转录抑制中的作用如何，TRIM28 与 L1 蛋白相互作用并刺激 L1 逆转录转座。 我们假设 AD 患者的基因组比正常人的基因组有更多的 pL1 受试者，这可能导致与 L1 相关的增加相关的神经元损失 DNA 损伤，尤其是与 TRIM28 失调结合时。我们将检验我们的假设 通过两个具体目标。目标 1 将进行病例对照研究以确定 AD患者（病例）和无认知能力的年龄匹配受试者基因组中的pL1 损害（控制）。这个目标将决定 pL1 的数量和/或组成是否是 与AD有关。目标 2 将确定 TRIM28 与 L1 ORF2p 相互作用的机制 蛋白质及其对 L1 整合和 DSB 形成的影响。这个目标将决定是否 TRIM28 在 L1 扩增循环和 TRIM28 相关机制中发挥双重作用 刺激 L1 逆转录转座。这些目标的综合积极成果将证明 大规模研究测试基因组 L1 内容在识别个体风险方面的效用 患有 AD 和/或其他与年龄相关的痴呆症。