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累，构成了其中的一个定义