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 蛋白在神经元病变中积聚并构成决定性因素之一 阿尔茨海默病和相关 tau 蛋白病的诊断标志。 Tau 神经病理学相关性 与阿尔茨海默氏病痴呆的严重程度有关。然而，tau 相关功能障碍和聚集驱动 由不完全了解的分子机制引起的神经退行性变化。之前的作品有 证明 RNA 结合蛋白影响模型系统和疾病中的 tau 功能和聚集 州。在定量研究中，我们发现 tau 与 RNA 的结合具有高亲和力，但序列特异性较低。 Tau RNA 复合物 (TRC) 形成高分子量寡聚 tau 物种，可能正在通往 形成成熟的纤维聚集体。我们生产了TRC识别单克隆抗体（TRC35） 检测疾病相关的病理 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、原纤维沉积和 神经变性而 MT 结合促进神经元稳态。我们提出3个具体目标来确定 tau RNA 结合活性对疾病发病机制的影响。我们将1）剖析分子特征 tau RNA 结合活性以及与 tau 微管结合活性的相互作用； 2）绘制丰度图， tau蛋白病疾病中TRC35+病变的分布和组成； 3）衡量影响 tau RNA 复合物的形成对神经​​退行性变的影响。拟议项目的完成将影响该领域 通过将 tau RNA 结合功能与 MT 稳定中已知的 tau 作用整合起来。我们也将获得显着的 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 tau蛋白病中观察到的神经变性。