Defining molecular contributions of LINE-1 retrotransposons to AD / ADRD

定义 LINE-1 逆转录转座子对 AD / ADRD 的分子贡献

• 批准号: 10701914
• 负责人: John Paul LaCava
• 金额: $ 74.62万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10701914
• 关键词: Age; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Astrocytes; Autopsy; Biological; Biological Assay; Biological Models; Brain; Cause of Death; Cell Aging; Cell Culture Techniques; Cell Nucleus; Cells; Cerebrospinal Fluid; Chromosomal Instability; Chronic stress; Clinical; Cytoplasm; Cytoplasmic Granules; Cytosol; DNA; DNA Damage; DNA replication fork; Data; Detection; Deterioration; Disease; Double-Stranded RNA; Elderly; Endogenous Retroviruses; Enzymes; Exhibits; Fibroblasts; Freezing; Frontotemporal Dementia; Functional disorder; Genes; Genome; Genomics; Growth Factor; Homeostasis; Human; Hybrids; Immunity; Immunoprecipitation; Impaired cognition; In Vitro; Individual; Induced pluripotent stem cell derived neurons; Inflammation; Inflammatory; Integration Host Factors; Interferons; Knowledge; Label; Lewy Body Dementia; Life; Life Cycle Stages; Location; Mass Spectrum Analysis; Modeling; Molecular; Molecular Genetics; Motivation; Mus; Neurodegenerative Disorders; Neurons; Normal Cell; Nucleic Acids; Onset of illness; Parasites; Pathologic; Pathology; Pathway interactions; Patients; Phase; Phenotype; Physiological; Play; Production; Property; Proteins; RNA; RNA Interference; RNA-Directed DNA Polymerase; RNA-Protein Interaction; Reactive Oxygen Species; Research; Retrotransposon; Ribonucleoproteins; Role; Sampling; Selfish DNA; Shotguns; Source; System; Techniques; Tissues; Titrations; age related; age related neurodegeneration; aged; brain tissue; candidate selection; cytokine; derepression; endonuclease; fly; genome integrity; immunogenic; improved; induced pluripotent stem cell; normal aging; overexpression; pathological aging; prevent; protein expression; senescence; tau Proteins

Project Summary: Alzheimer's Disease (AD) and AD-related dementias (ADRDs; e.g. Frontotemporal Dementia, Lewy Body Dementia, etc.) are crippling neurodegenerative disorders. The onset of these diseases is strongly correlated with aging. Cures for AD and ADRDs remain elusive; Alzheimer's has become the 6th most frequent cause of death in the USA. An emerging candidate contributor to Alzheimer's and ADRD is the L1 retrotransposon, which becomes dysregulated during aging and correlates with Alzheimer's / ADRD onset. One hypothetical mechanism by which L1 may contribute to Alzheimer's / ADRD is through its exacerbation of cellular senescence. Senescence is a phenomenon by which normal cells stop dividing; these cells accumulate with advancing age and are found at the locations of dysfunction in age-related diseases. In mice, senescent cells have been shown to shorten life and actively drive age-related neurodegeneration; preventing senescent cell accumulation decreases tau-dependent degeneration and cognitive decline. AD patients exhibit increased indicators of cellular senescence. It is increasingly clear that senescent cells are not inert, but instead drive tissue deterioration via the senescence-associated secretory phenotype - secreting a variety of growth factors and pro- inflammatory cytokines. L1 retrotransposons have recently been shown to drive progression of the senescence- associated secretory phenotype, and thus, L1 is an important agent of cellular senescence. L1 activation is also associated with AD-related Tau pathologies. The L1 encoded ORF2p enzyme (endonuclease and reverse transcriptase) is often flagged as a source of pathological cellular insults, e.g. via new, mutagenic L1 insertions and contributions to chromosomal instability. However, the effects of L1 expression extend beyond DNA damage. Numerous mechanisms may be at play, including the titration of normally homeostatic host factors away from their physiologic functions and into L1 ribonucleoprotein granules, as well as the production of immunity-and-inflammation-triggering cytoplasmic L1 DNA:RNA hybrids; indeed, the latter is now understood to be a key component of L1’s role in cellular senescence. Moreover, L1 also mobilizes Alu and other non- autonomous retrotransposons. Objectives: In Aim 1, we will use targeted mass spectrometry to profile L1 ORF1 protein expression in the cerebrospinal fluid (CSF) and post-mortem brain tissues of patients exhibiting AD/ADRD and cognitive decline, as well as in senescent cells and neuronal iPSCs; in Aim 2 (in vitro cell culture) and Aim 3 (clinical samples) we will profile L1-associated protein-protein and protein-RNA interactions in the same biological samples as Aim 1; and in Aim 4 we will take a candidate-based approach using molecular genetics to dissect the mechanisms of action of L1 in senescent cells.

项目摘要：阿尔茨海默氏病（AD）和广告相关痴呆症（ADRDS;例如额颞 痴呆症，刘易体内痴呆等是哭泣的神经退行性疾病。这些疾病的发作 与衰老密切相关。 AD和ADRD的治疗方法仍然难以捉摸；阿尔茨海默氏症已成为第六名 在美国经常死亡。新兴候选人为阿尔茨海默氏症和ADRD贡献者是L1 逆转录座子在衰老期间失调，与阿尔茨海默氏症 / ADRD发作相关。一 L1可能导致阿尔茨海默氏症 / ADRD的假设机制是通过其加剧的细胞来 衰老。衰老是正常细胞停止分裂的现象。这些细胞随着 在与年龄有关的疾病功能障碍的位置发现年龄，并在与年龄有关的疾病中发现。在小鼠中，感觉细胞 已显示出缩短寿命并积极驱动与年龄相关的神经变性。防止感觉细胞 积累下降了tau依赖性变性和认知能力下降。广告患者暴露了 细胞感应的指标。越来越明显的是，感觉细胞不是惰性的，而是驱动组织 通过感应相关的秘书表型恶化 - 分泌多种生长因子和促进 炎症细胞因子。最近已显示L1逆转座子驱动衰老的进展 相关的秘密表型，因此L1是细胞感应的重要药物。 L1激活也是 与广告相关的TAU病理相关。 L1编码的ORF2P酶（核酸内切酶和反向 转录酶通常被标记为病理细胞插入片段的来源，例如通过新的诱变L1插入 并导致染色体不稳定性。但是，L1表达的影响延伸到DNA之外 损害。可能有许多机制在起作用，包括通常稳态宿主因素的滴定 远离其生理功能，进入L1核糖核蛋白颗粒，并产生 免疫和炎症触发细胞质L1 DNA：RNA杂种；确实，后者现在已经理解 成为L1在细胞感应中作用的关键组成部分。此外，L1还动员了Alu和其他非 - 自动逆转座子。 目标：在AIM 1中，我们将使用靶向的质谱法来配置L1 ORF1蛋白表达 表现出AD/ADRD和认知能力下降的患者的脑脊液（CSF）和验尸后脑组织 以及在感觉细胞和神经元IPSC中；在AIM 2（体外细胞培养）和AIM 3（临床样本）中 将在与AIM 1相同的生物样品中介绍与L1相关的蛋白质蛋白质和蛋白RNA相互作用； 在AIM 4中，我们将使用分子遗传学采取一种基于候选的方法来剖析 L1在感觉细胞中的作用。