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的方法，称为