ELUCIDATING AN INHIBITORY ROLE OF MAP2 IN TAU FIBRILLIZATION

阐明 MAP2 在 TAU 纤维化中的抑制作用

• 批准号: 9763419
• 负责人: Martin Margittai
• 金额: $ 18.46万
• 依托单位: UNIVERSITY OF DENVER (COLORADO SEMINARY)
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9763419
• 关键词: Affect; Alzheimer' s Disease; Binding; Brain; Brain Diseases; Cells; Data; Deposition; Disease; Foundations; Future; Goals; Growth; Human; Individual; Investigation; Knowledge; Laboratories; Lead; Length; Light; Mediating; Microtubule-Associated Protein 2; Microtubules; Mission; Molecular; Molecular Conformation; Neurodegenerative Disorders; Neurons; Outcome; Pathologic; Pathology; Pathway interactions; Pharmaceutical Preparations; Phenotype; Population; Prevention; Prevention strategy; Preventive; Prions; Proteins; Public Health; Reporting; Research; Role; Sequence Homology; Structure; Tauopathies; Testing; Therapeutic; Therapeutic Intervention; United States; United States National Institutes of Health; Variant; Work; base; beta pleated sheet; conformer; inhibitor/antagonist; innovation; insight; monomer; novel strategies; novel therapeutic intervention; pressure; recruit; tau Proteins; tau aggregation

Currently, there are no drugs that halt the progression of Alzheimer's disease (AD). This constitutes an important problem because >5 million people in the United Sates are affected. The deposition of Tau fibrils throughout the brain is a pathological hallmark of the disease. Targeting the fibrils holds promise for therapeutic intervention. MAP2 is a protein that is highly homologous to Tau and is found in close proximity to Tau deposits. The objective of this proposal is to determine how MAP2 modulates Tau fibril formation. The central hypothesis is that MAP2 caps Tau fibrils at the ends and thereby inhibits fibril growth. This hypothesis has been formulated based on data produced in the applicant's laboratory that reveals specific interactions between Tau fibrils and MAP2. The rationale is that once the modulatory roles of MAP2 are resolved, new strategies can be developed that utilize MAP2 as a blocking agent of Tau fibril formation. Supported by strong preliminary data the central hypothesis will be tested by pursuit of the following three specific aims. 1) Evaluate the inhibitory effects of MAP2 on the elongation of AD-derived Tau fibrils. 2) Identify the molecular mechanism of MAP2-mediated inhibition. 3) Determine how MAP2 modulates the propagation of distinct Tau fibril conformers. The research is innovative because it establishes an endogeneous protein with high sequence homology to Tau as a potent new inhibitor of Tau fibrillization. The proposed research is significant because it is expected to lead to new strategies for the prevention and treatment of a wide range of Tau misfolding diseases including AD. The research is exploratory and lays the foundation for future studies into the phenotypic diversity of human Tauopathies and novel therapeutic approaches that utilize homology-based inhibition of Tau fibrillization.

目前，还没有药物可以阻止阿尔茨海默病（AD）的进展。这构成了 这是一个重要的问题，因为美国有超过500万人受到影响。Tau纤维的沉积 是这种疾病的病理标志靶向纤维有望 治疗干预MAP2是一种与Tau高度同源的蛋白质，并且发现与Tau非常接近。 Tau存款。该提议的目的是确定MAP 2如何调节Tau原纤维形成。的 中心假设是MAP2在末端给Tau原纤维加帽，从而抑制原纤维生长。这一假设 已根据申请人实验室产生的数据制定，这些数据揭示了特定的相互作用 Tau纤维和MAP 2之间的联系基本原理是，一旦MAP 2的调节作用被解决， 可以开发利用MAP 2作为Tau原纤维形成的阻断剂的策略。强大的支持 初步数据中心假设将通过追求以下三个具体目标进行检验。1)评价 MAP 2对AD衍生的Tau原纤维延伸的抑制作用。2)确定分子机制 MAP2介导的抑制。3)确定MAP2如何调节不同Tau原纤维的增殖 构象异构体这项研究是创新的，因为它建立了一个高序列的内源性蛋白质 与Tau同源，作为Tau凝血的有效的新抑制剂。这项研究意义重大，因为它 有望为预防和治疗广泛的Tau错误折叠带来新的策略 疾病包括AD。本研究具有探索性，为今后的研究奠定了基础。 人类Tau病的表型多样性和利用基于同源性的 抑制Tau纤维化。

项目成果

MAP2 caps tau fibrils and inhibits aggregation.

• DOI: 10.1016/j.jbc.2023.104891
• 发表时间: 2023-07
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Holden, Michael R.;Krzesinski, Brad J.;Weismiller, Hilary A.;Shady, Justin R.;Margittai, Martin
• 通讯作者: Margittai, Martin