Contributions of tau-mediated translational dysregulation to pathogenesis and progression of fronto-temporal dementia

tau 介导的翻译失调对额颞叶痴呆发病机制和进展的影响

• 批准号: 10370091
• 负责人: Jose Francisco Abisambra
• 金额: $ 58.75万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10370091
• 关键词: Affect; Affinity; Alzheimer' s Disease; Biological Assay; Brain; Cell physiology; Cells; Chromosome 17; Cognitive; Complex; Data; Dementia; Development; Disease; Frontotemporal Dementia; Functional disorder; Future; Genetic; Goals; Human; Impairment; In Vitro; Individual; Knockout Mice; Knowledge; Link; Maps; Measures; Mediating; Memory; Memory Loss; Memory impairment; Messenger RNA; Microtubule Stabilization; Mission; Modeling; Molecular; Mus; Mutation; Neuronal Dysfunction; Organ; Pathogenesis; Pathologic; Persons; Physiologic pulse; Protein Biosynthesis; Proteins; Proteomics; Publishing; Puromycin; RNA; RNA-Binding Proteins; Recombinant Proteins; Recombinants; Regulation; Research; Ribosomal Interaction; Ribosomal Proteins; Ribosomes; Risk; Screening procedure; Symptoms; Tauopathies; Testing; Transcript; Translating; Translational Repression; Translations; United States National Institutes of Health; Veterans; Work; aging population; base; brain dysfunction; brain tissue; common symptom; design; effective therapy; high risk; in vitro Model; in vivo; in vivo Model; innovation; mouse model; novel; novel therapeutic intervention; overexpression; targeted treatment; tau Proteins; tau aggregation; tau expression; tau mutation; therapeutic target; trafficking; translation factor; translatome; virtual

Abstract There is a fundamental gap in understanding how mutations on P301 of tau cause memory impairment in fronto-temporal dementia (FTD). One pathological mechanism involves the association of aberrant tau with ribosomal complexes. However, the consequences of this interaction are unknown. The long-term goal of this work is to better understand the link between tau P301 mutations and memory impairment in FTD. The objective of this proposal is to determine the impact of mutant tau on translation. We will use human brain tissues as well as in vitro and in vivo models to study ribosomes in isolation, translation in cells, and brain pathophysiology in mice. Our preliminary results substantiate that the association between tau and ribosomal complexes impair protein synthesis. Therefore, the central hypothesis is that pathological tau inhibits translation of proteins critical for memory. The rationale for the proposed research is that understanding the tau-mediated mechanism of ribosomal dysfunction will aid in the design of therapeutic targets for FTD, which currently afflict a vast amount of individuals. Our strong preliminary data serves as support for testing the hypotheses that 1) pathological tau engages with different parts of the ribosome, 2) translational repression is present in various in vivo tau models. and 3) the ribosomes’ affinity for transcripts, capacity, and efficiency are impaired in human FTD brains. These aims have the potential of extrinsic merit to be used as screening tools for modulators of ribosomal function. Our approach is innovative because it incorporates novel assays, which offer excellent sensitivity that is not achievable by more traditional approaches. This work is significant because it departs from the status quo by testing a new mechanism in which translation dysfunction mediates tauopathic symptoms. This work is expected to advance the field by filling the gap in understanding of tau-mediated brain dysfunction. This knowledge will serve to better characterize the link between tau and memory impairment in order to develop novel therapeutic strategies.

摘要 在理解tau基因P301突变如何导致记忆障碍方面存在着根本的空白 额颞性痴呆(FTD)。一种病理机制涉及异常tau与 核糖体复合体。然而，这种互动的后果尚不清楚。这样做的长期目标是 工作是为了更好地了解tau P301突变和FTD记忆障碍之间的联系。目标是 这一建议的目的是确定突变tau对翻译的影响。我们也将使用人脑组织 作为体外和体内模型，研究核糖体的分离，细胞内翻译和脑病理生理学 老鼠。我们的初步结果证实，tau和核糖体复合体之间的联系损害了 蛋白质合成。因此，中心假设是病理性tau抑制关键蛋白质的翻译。 为了记忆。这项拟议研究的基本原理是，理解tau介导的机制 核糖体功能障碍将有助于设计FTD的治疗靶点，目前FTD正遭受着巨大的痛苦 关于个人的。我们强劲的初步数据支持了以下假设：1)病理性牛磺酸 与核糖体的不同部分接触，2)翻译抑制存在于体内的各种tau中 模特们。3)人类FTD核糖体对转录本的亲和力、能力和效率受损 大脑。这些目标有可能被用作核糖体调节子的筛选工具。 功能。我们的方法是创新的，因为它结合了新的分析方法，提供了出色的灵敏度， 通过更传统的方法是无法实现的。这项工作意义重大，因为它偏离了现状 通过测试一种新的机制，在这种机制中，翻译功能障碍调节了紧张症症状。这项工作是 有望通过填补tau介导的脑功能障碍的理解空白来推动这一领域的发展。这 知识将有助于更好地描述tau和记忆损害之间的联系，以便发展 新的治疗策略。