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聚，构成了 阿尔茨海默病和相关的肌萎缩侧索硬化症的诊断特征。Tau神经病理与 与阿尔茨海默病的痴呆症严重程度有关。然而，tau相关的功能障碍和聚集驱动 神经退行性改变的分子机制还不完全清楚。以前的工作有 证明RNA结合蛋白在模型系统和疾病中影响tau的功能和聚集 各州。在定量研究中，我们已经证明tau以高亲和力但低序列特异性结合RNA。 Tau RNA复合体(Trc)形成高分子量低聚tau物种，它可能在途径上 形成成熟的纤维状聚集体。我们研制了一种可识别TRC的单抗(TRC35)。 检测到与疾病相关的病理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堆积、纤维沉积和 神经退行性变，而MT结合促进神经元动态平衡。我们提出了三个具体目标来确定 Tau RNA结合活性在疾病发病机制中的影响。我们将1)剖析它的分子特征 Tau RNA结合活性及其与tau微管结合活性的相互作用；2)绘制丰度图， TRC35+病变在肌萎缩侧索硬化症中的分布和组成；以及3)测量 Tau RNA复合体的形成对神经退变的影响。拟议项目的完成将对该油田产生影响 通过整合tau RNA结合功能和已知的tau在MT稳定中的作用。我们还将获得显著的收益 了解与疾病相关的病理性tau聚集和 肌张力障碍中的沉积。我们将进一步测量tau/RNA复合体对 在神经官能症中观察到的神经变性。