Elucidating the Roles of Transposable Elements in Alzheimer's and related dementias

阐明转座元件在阿尔茨海默病和相关痴呆症中的作用

• 批准号: 10518654
• 负责人: PENG JIN
• 金额: $ 77.75万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10518654
• 关键词: 3-Dimensional; Affect; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Alzheimer' s disease related dementia; American; Amyloid beta-Protein; Amyotrophic Lateral Sclerosis; Astrocytes; Autopsy; Binding; Biological; Biological Models; Brain; Brain region; Cell Nucleus; Cell Separation; Cells; Chromatin; Clinical; Cognition; DNA; DNA Binding; DNA Sequence; DNA Transposable Elements; DNA Transposons; DNA-Binding Proteins; Data; Development; Diagnosis; Disease; Disease Progression; Elements; Epigenetic Process; Event; Genetic Transcription; Genome Stability; Genomic Instability; Goals; Homeostasis; Human; Human Genome; Hybrids; Knowledge; Language; Light; Link; Maintenance; Mediating; Memory; Messenger RNA; Metabolism; Modeling; Molecular; Molecular Target; Neuraxis; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Nuclear; Organoids; Pathogenesis; Pathologic; Patients; Play; Prefrontal Cortex; Process; Prosencephalon; Publications; RNA; RNA Binding; RNA-Binding Proteins; Regulation; Reporting; Role; Senile Plaques; Structure; System; Technology; Temporal Lobe; Testing; Therapeutic; Transcriptional Regulation; Translating; abeta accumulation; abeta oligomer; age related; age related neurodegeneration; cell type; clinical phenotype; clinically relevant; effective intervention; familial Alzheimer disease; genome integrity; genome-wide; human disease; human model; improved; induced pluripotent stem cell; insight; interest; knock-down; loss of function; mammalian genome; molecular phenotype; mouse model; neurotoxicity; novel; nucleic acid structure; prognosis biomarker; protein TDP-43; protein aggregation; protein misfolding; tau Proteins; therapeutically effective; tool; transcriptome; translational therapeutics

Project Summary AD is an age-related progressive neurodegenerative disorder affecting millions of Americans without effective interventions. The gradual accumulation of neurofibrillary tangles formed by abnormal protein aggregation, such as tau and amyloid-β (Aβ) protein, serves as the neuropathological hallmark of AD. In recent years, the role of TAR DNA-binding protein 43 (TDP-43), a DNA and RNA-binding protein that has been heavily studied in amyotrophic lateral sclerosis (ALS) and fronto-temporal lobar degeneration (FTLD-TDP), has drawn increasing interest for AD pathogenesis. The pathological role of TDP-43 can be attributed to both its neurotoxicity in AD brain caused by its increased pathological aggregation in various brain regions such as the cortex and its loss of normal function in the central nervous system. However, the detailed mechanistic role underlying TDP-43 mediated AD progression remains elusive. One established biological role of TDP-43 is to regulate the expression of transposon elements (TEs), highly repetitive DNA sequences that occupy more than half of human genome. A hallmark of TEs is that they harbor a three-stranded DNA:RNA hybrid structure referred to as R- loops, which have been linked to a wide variety of biological events, such as transcriptional regulation and genomic stability maintenance. Recent publications, along with our preliminary data, suggest a direct role of TDP-43 in regulating R-loop formation. Our long-term goals are to elucidate the role of TDP-43, via R-loop regulation, for controlling TE expression in age-related neurodegeneration, and to translate our findings into clinically relevant strategies for the improved treatment of AD. In this application, we focus on how TDP-43 loss- of-function results in altered TE expression and leads to AD pathogenesis. Our exciting preliminary data suggest: 1) Global alteration of TE expression and associated changes of the R-loop landscape are observed in human AD postmortem brains and are distinctive from AD mouse model; 2) Evolutionarily younger TEs show higher expression levels and stronger R-Loop enrichment than more ancient TEs, in general, and they also harbor more drastic TE/R-loops changes in AD brains; 3) Stable depletion of TDP-43 in neuronal cells leads to aberrant R- loop alterations in TEs, concurrent with altered TE expression and 5hmC profiling; 4) TDP-43 directly binds to a subset of TEs in neuronal cells which overlap with AD associated TEs, and 5) AD patient derived 3D cortical organoids corroborate cellular and molecular phenotypes of AD, serving as an excellent human model system. We will test the hypothesis that TDP-43 plays an important role in modulating TE expression via R-loop regulation, and TE dysregulation due to TDP-43 loss-of-function is critical for AD pathogenesis. Findings from these studies will provide unique mechanistic insights into the fundamental rules of TE expression regulation by TDP-43, which has the potential to discover new molecular targets with relevant clinical, translational, and therapeutic implications.

项目概要 AD 是一种与年龄相关的进行性神经退行性疾病，影响着数百万美国人，但没有有效的治疗方法 干预措施。由异常蛋白质聚集形成的神经原纤维缠结逐渐积累，例如 tau 蛋白和β-淀粉样蛋白 (Aβ) 是 AD 的神经病理学标志。近年来，所扮演的角色 TAR DNA 结合蛋白 43 (TDP-43)，一种 DNA 和 RNA 结合蛋白，已在 肌萎缩侧索硬化症 (ALS) 和额颞叶变性 (FTLD-TDP) 已引起越来越多的关注 对 AD 发病机制的兴趣。 TDP-43 的病理作用可归因于其在 AD 中的神经毒性 由于其在各个大脑区域（例如皮质）的病理性聚集增加及其损失而引起的大脑 中枢神经系统的正常功能。然而，TDP-43 的详细机制作用 介导的 AD 进展仍然难以捉摸。 TDP-43 的一项已确定的生物学作用是调节 转座子元件（TE）的表达，高度重复的DNA序列占据了人类一半以上 基因组。 TE 的一个标志是它们具有三链 DNA:RNA 混合结构，称为 R- 环，与多种生物事件有关，例如转录调控和 基因组稳定性维护。最近的出版物以及我们的初步数据表明， TDP-43 调节 R 环形成。我们的长期目标是通过 R 环阐明 TDP-43 的作用 调节，用于控制年龄相关神经变性中的 TE 表达，并将我们的发现转化为 改善 AD 治疗的临床相关策略。在此应用中，我们重点关注 TDP-43 如何损失- 功能失调导致 TE 表达改变并导致 AD 发病机制。我们令人兴奋的初步数据表明： 1) 在人类中观察到 TE 表达的整体改变以及 R 环景观的相关变化 AD死后大脑与AD小鼠模型不同； 2) 进化上越年轻的TE表现得越高 一般来说，与更古老的 TE 相比，它们的表达水平和更强的 R-Loop 富集，并且它们还包含更多 AD 大脑中的 TE/R 环发生剧烈变化； 3) 神经元细胞中TDP-43的稳定消耗导致R-异常 TE 中的环改变，与改变的 TE 表达和 5hmC 分析同时发生； 4) TDP-43直接结合 神经元细胞中与 AD 相关 TE 重叠的 TE 子集，以及 5) AD 患者衍生的 3D 皮质 类器官证实了 AD 的细胞和分子表型，是一个优秀的人类模型系统。 我们将检验 TDP-43 在通过 R 环调节 TE 表达中发挥重要作用的假设 TDP-43 功能丧失导致的 TE 失调对于 AD 发病机制至关重要。发现 这些研究将为 TE 表达的基本规则提供独特的机制见解 TDP-43的调控，有潜力发现具有相关临床、 转化和治疗意义。