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

摘要 在理解tau蛋白的P301突变如何导致记忆障碍方面存在根本性的空白。 额颞叶痴呆（FTD）。一种病理机制涉及异常tau蛋白与 核糖体复合物然而，这种相互作用的后果是未知的。长期目标是 这项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。客观 该建议的目的是确定突变tau蛋白对翻译的影响。我们也会用人脑组织 作为体外和体内模型来研究核糖体的分离、细胞中的翻译和脑病理生理学， 小鼠我们的初步结果证实了tau蛋白和核糖体复合物之间的关联损害了 蛋白质合成因此，中心假设是病理性tau蛋白抑制了关键蛋白质的翻译， 为了记忆这项研究的基本原理是，了解tau蛋白介导的 核糖体功能障碍将有助于设计FTD的治疗靶点，目前FTD正在折磨着大量的 个人。我们强有力的初步数据支持了以下假设：1）病理性tau蛋白 与核糖体的不同部分接合，2）翻译抑制存在于各种体内tau蛋白中， 模型和3）在人FTD中，核糖体对转录物的亲和力、能力和效率受损 大脑这些目标具有潜在的外在价值，可用作核糖体蛋白调节剂的筛选工具。 功能我们的方法是创新的，因为它结合了新的检测方法，提供了出色的灵敏度， 这是传统方法无法实现的。这项工作意义重大，因为它脱离了现状 通过测试一种新的机制，其中翻译功能障碍介导tau蛋白病症状。这项工作是 有望通过填补对tau介导的脑功能障碍的理解的差距来推进该领域。这 知识将有助于更好地表征tau蛋白和记忆障碍之间的联系， 新的治疗策略。

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.