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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease patient Alzheimer&apos 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

项目摘要

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.

项目摘要 AD是一种与年龄相关的进行性神经退行性疾病，影响数百万美国人而没有有效干预措施。由异常蛋白质聚集形成的神经原纤维缠结的等级积累，作为tau和淀粉样蛋白（Aβ）蛋白，作为AD的神经病理标志。近年来， TAR DNA结合蛋白43（TDP-43），一种DNA和RNA结合蛋白，已大量研究肌萎缩性侧索硬化症（ALS）和额叶LOBAR变性（FTLD-TDP）已吸引 AD发病机理的兴趣。 TDP-43的病理作用可以归因于其在AD中的神经毒性大脑是由于其在皮层等各个大脑区域的病理聚集增加而引起的中枢神经系统正常功能。但是，TDP-43的详细机械作用介导的广告进展仍然难以捉摸。 TDP-43的一个已建立的生物学作用是调节转座子元件（TES）的表达，高度重复的DNA序列，占据了一半以上的人基因组。 TES的标志是它们具有三链DNA：RNA杂交结构，称为R- 循环与各种生物事件有关，例如转录调节和基因组稳定性维持。最近的出版物以及我们的初步数据表明 TDP-43在调节R环的形成中。我们的长期目标是通过R环阐明TDP-43的作用调节，用于控制与年龄相关的神经变性中的TE表达，并将我们的发现转化为临床相关的策略，用于改善AD的治疗。在此应用中，我们关注TDP-43损失如何功能会导致TE表达改变并导致AD发病机理。我们令人兴奋的初步数据表明： 1）在人类中观察到TE表达的全球变化和R-loop景观的相关变化广告后大脑，与AD小鼠模型不同； 2）进化上年轻的TE显示较高总体而言，表达水平和更强的R环富集比更古老的TE 广告大脑的急剧变化； 3）TDP-43在神经元细胞中的稳定部署导致异常R- TES中的循环改变，与TE表达和5HMC分析的改变； 4）TDP-43直接与A结合与AD相关TE重叠的神经元细胞中TE的子集，5）AD患者衍生3D皮质类器官证实了AD的细胞和分子表型，它是一种出色的人类模型系统。我们将检验以下假设，即TDP-43在通过R环调节TE表达中起重要作用 TDP-43功能丧失引起的调节和te失调对于AD发病机理至关重要。发现从这些研究中，将为TE表达的基本规则提供独特的机械见解 TDP-43的调节，有可能发现具有相关临床的新分子靶标的翻译和治疗意义。