Seeds and Strains Derived from Tau Monomer - Perez Diversity Supplement

Tau 单体衍生的种子和菌株 - Perez Diversity Supplement

基本信息

批准号：
10300865
负责人：
MARC I DIAMOND
金额：
$ 6.47万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2024-08-31
项目状态：
已结题

项目摘要

PROJECT SUMMARY/ABSTRACT Alzheimer disease (AD) and related tauopathies are major diagnostic, therapeutic, and clinical challenges. Our previous work suggest that different tauopathies are based on unique tau aggregate conformations, or “strains,” and that strain identity predicts specific disease progression patterns in animal models. We hypothesize that distinct, self-propagating tau strains can move between cells of the brain to propagate pathology in humans. Recent publications from our group indicate that tau monomer in fact encodes strains. However this has not been rigorously tested across tauopathies. We will test this idea first by determining whether tau monomer encodes the same sets of strains encoded by larger assemblies in human brain (Aim 1). Next we will use multiplex biosensors to classify monomer from human tauopathies, and determine whether monomer can classify individuals in correlation with neuropathology with the same fidelity as larger assemblies. We will also test the fidelity of strain propagation in human neurons vs. HEK293 cells in comparison those strains isolated directly from human brain (Aim 2). Finally, we use structural biology approaches to determine the conformations of seed-competent monomer. In particular, we will determine whether local structures in tau predict its subsequent assembly into fibrils. This will be based on crosslinking mass spectrometry, molecular modeling, cryoEM, and microcrystallography. We predict that tau monomer will encode strain composition across tauopathies. If we are successful, we anticipate ultimately that it will be possible to classify tauopathies based on the conformation with tau monomer. This could have important implications for accurate diagnosis and personalized therapy.

项目摘要/摘要阿尔茨海默氏病（AD）和相关的呼吸病是主要的诊断，治疗和临床挑战。我们以前的工作表明，不同的tauopathies是基于独特的tau骨料构象或“菌株”，以及应变身份预测特定疾病进展模式动物模型。我们假设独特的自我传播的tau菌株可以在大脑在人类中传播病理学。我们小组的最新出版物表明tau 实际上，单体编码菌株。但是，这并未在跨tauopathies进行严格测试。我们将首先通过确定tau单体是否编码相同的菌株来测试这个想法由人脑中较大的组件编码（AIM 1）。接下来，我们将使用多个生物传感器来对人的tauopathies分类单体，并确定单体是否可以对个体进行分类与神经病理学的相关性与较大的组件相同的忠诚度。我们还将测试相比之下直接来自人脑（目标2）。最后，我们使用结构生物学方法来确定种子能力单体的构象。特别是，我们将确定本地结构是否在tau中，随后的组装将其分为原纤维。这将基于交联质量光谱，分子建模，冷冻和微晶学。我们预测Tau单体将跨金刚病编码应变组成。如果我们成功，我们最终会预期可以根据与Tau单体的构象对tauopathies进行分类。这可能会有对准确的诊断和个性化治疗的重要意义。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

DnaJC7 specifically regulates tau seeding.

DOI：
10.7554/elife.86936
发表时间：
2023-06-30
期刊：
eLife
影响因子：
7.7
作者：
Perez VA;Sanders DW;Mendoza-Oliva A;Stopschinski BE;Mullapudi V;White CL;Joachimiak LA;Diamond MI
通讯作者：
Diamond MI

Seed-competent tau monomer initiates pathology in a tauopathy mouse model.

DOI：
10.1016/j.jbc.2022.102163
发表时间：
2022-08
期刊：
JOURNAL OF BIOLOGICAL CHEMISTRY
影响因子：
4.8
作者：
Mirbaha, Hilda;Chen, Dailu;Mullapudi, Vishruth;Terpack, Sandi Jo;White, Charles L.;Joachimiak, Lukasz A.;Diamond, Marc, I
通讯作者：
Diamond, Marc, I

The interactions that shape amyloid fibrils in disease.

疾病中形成淀粉样原纤维的相互作用。