Formation of Tau RNA Complexes disrupts tau function and drives tau neuropathology

Tau RNA 复合物的形成会破坏 tau 功能并驱动 tau 神经病理学

• 批准号: 10777174
• 负责人: Brian C. Kraemer
• 金额: $ 63.88万
• 依托单位: SEATTLE INST FOR BIOMEDICAL/CLINICAL RES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10777174
• 关键词: Affinity; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Amyloid; Automobile Driving; Binding; Biological Models; Brain; Brain Diseases; Caenorhabditis elegans; Cells; Cessation of life; Characteristics; Clinical Trials; Cognitive; Complex; Data; Dementia; Deposition; Diagnostic; Disease; Frontotemporal Lobar Degenerations; Functional disorder; Genes; Homeostasis; Human; Impaired cognition; Intervention; Knowledge; Lesion; Maps; Measures; Mediating; Mediator; Messenger RNA; Microtubule Polymerization; Microtubule Stabilization; Microtubules; Molecular; Molecular Conformation; Molecular Weight; Monitor; Monoclonal Antibodies; Nerve Degeneration; Neuronal Dysfunction; Neurons; Outcome; Pathogenesis; Pathologic; Pathology; Pathway interactions; Poly(A) Tail; Poly(A)+ RNA; Predisposition; Property; Protein Isoforms; Proteins; RNA; RNA Binding; RNA Recognition Motif; RNA-Binding Proteins; Reporter; Role; Severities; Specificity; System; Tauopathies; Therapeutic; Toxic effect; Transgenes; Tubulin; Work; brain tissue; disability; in vivo; mouse model; neuropathology; polyadenylated messenger RNA; pre-clinical; preservation; symptom treatment; targeted treatment; tau Proteins; tau aggregation; tau conformation; tau function; tau mutation; therapeutic development; tool

Pathological tau protein accumulates in neuronal lesions and constitutes one of the defining diagnostic hallmarks of Alzheimer’s disease and related tauopathy disorders. Tau neuropathology correlates with severity of dementia in Alzheimer’s disease. However, tau related dysfunction and aggregation drives neurodegenerative changes by an incompletely understood molecular mechanism. Previous work has demonstrated that RNA binding proteins impact tau function and aggregation in model systems and disease states. In quantitative studies, we have shown that tau binds RNA with high affinity but low sequence specificity. Tau RNA complexes (TRCs) form high molecular weight oligomeric tau species that may be on pathway to formation of mature fibrillar aggregates. We have produced a TRC recognizing monoclonal antibody (TRC35) that detects a disease relevant pathological tau conformation. We hypothesize that RNA and microtubules (MTs) compete for tau binding with TRC formation driving neuropathological tau accumulation, fibril deposition, and neurodegeneration while MT binding promotes neuronal homeostasis. We propose 3 specific aims to determine the impact of tau RNA binding activity on disease pathogenesis. We will 1) dissect the molecular features of tau RNA binding activity and interplay with tau microtubule binding activity; 2) map the abundance, distribution, and composition of TRC35+ lesions in tauopathy disorders; and 3) measure the impact of tau RNA complex formation on neurodegeneration. Completion of the proposed project will impact the field by integrating tau RNA binding functions with known tau roles in MT stabilization. We will also gain significant understanding of the molecular mechanisms involved in disease relevant pathological tau aggregation and deposition in tauopathy disorders. We will further measure the contribution of tau/RNA complexes to the neurodegeneration observed in tauopathies.

病理性tau蛋白在神经元损伤中积累，并构成了决定性的神经元损伤之一。 阿尔茨海默病和相关tau蛋白病的诊断标志。Tau神经病理学相关 与阿尔茨海默病的痴呆程度相关。然而，tau蛋白相关的功能障碍和聚集驱动 神经退行性变化的分子机制尚未完全了解。先前的工作已经 证明RNA结合蛋白影响模型系统和疾病中的tau蛋白功能和聚集 states.在定量研究中，我们已经表明tau蛋白以高亲和力但低序列特异性结合RNA。 Tau RNA复合物（TRC）形成高分子量寡聚tau种类，其可能在与Tau RNA复合物（TRC）的途径上。 形成成熟的纤维状聚集体。我们制备了识别TRC的单克隆抗体（TRC 35）， 检测与疾病相关的病理性tau构象。我们假设RNA和微管（MT） 与TRC形成竞争tau结合，驱动神经病理性tau积累、原纤维沉积，以及 神经变性，而MT结合促进神经元稳态。我们提出了三个具体目标，以确定 tau RNA结合活性对疾病发病机制的影响。我们将1）剖析 tau RNA结合活性和与tau微管结合活性的相互作用; 2）绘制丰度， tau蛋白病病症中TRC 35+病变的分布和组成;以及3）测量以下因素的影响： tau RNA复合物的形成对神经变性的影响。拟议项目的完成将影响外地 通过将tau RNA结合功能与MT稳定中已知的tau作用整合。我们还将获得巨大的 了解疾病相关病理性tau聚集的分子机制， tau蛋白病疾病中的沉积。我们将进一步测量tau/RNA复合物对细胞凋亡的贡献。 在tau蛋白病中观察到的神经变性。