Atomic models of human tau filaments and development of tau ligands

人类 tau 丝的原子模型和 tau 配体的开发

• 批准号: 10470728
• 负责人: BERNARDINO Francesco GHETTI
• 金额: $ 67.73万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10470728
• 关键词: Address; Affect; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease related dementia; Amyloid; Amyloid beta-Protein; Argyrophilic Grain Disease; Binding; Binding Sites; Biochemical; Brain; Code; Collaborations; Cryoelectron Microscopy; Deposition; Development; Disease; FTD with parkinsonism; Family; Filament; Goals; Human; In Vitro; Indiana; Individual; Inherited; Laboratories; Lead; Ligands; Manufactured football; Maps; Modeling; Molecular; Molecular Biology; Morphology; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Pathologic; Pathology; Patients; Pick Disease of the Brain; Positron-Emission Tomography; Property; Protein Isoforms; Proteins; Recording of previous events; Role; Structure; Tauopathies; Tracer; Traumatic Brain Injury; Universities; Work; base; brain tissue; chronic traumatic encephalopathy; corticobasal degeneration; early detection biomarkers; human model; in vivo; in vivo imaging; interest; multidisciplinary; novel; paired helical filament; response; structural biology; tau Proteins; tau aggregation; tau mutation

Recently, significant progress has been made in understanding tauopathies and how tau aggregates lead to neurodegeneration by the first description of the atomic structures of tau filaments from Alzheimer’s disease (AD) brain. The atomic models for the core of paired helical filaments (PHFs) and straight filaments (SFs) purified from the brain of an individual with AD were determined by cryo-electron microscopy (cryo-EM) through an ongoing collaborative effort between our laboratory at Indiana University and the MRC Laboratory of Molecular Biology. The studies proposed in this MPI application are a logical continuation of this groundbreaking work. These studies are in response to RFA-NS-18-015 “Structural Biology of Alzheimer's Disease Related Dementias (ADRDs) Proteinopathies” (U01). Our proposal has 3 specific aims. The first is to generate a cryo-EM map and determine the corresponding atomic models of tau filaments from the brain of individuals with sporadic and hereditary 3R and 4R tauopathies, in a collaborative effort between the Vidal and Ghetti laboratories at Indiana University and the Jiang laboratory at Purdue University. Importantly, our efforts will have the full support of our collaborators at MRC, Drs. Goedert and Scheres. Second, we will generate a cryo-EM map and determine the corresponding atomic models of tau filaments from the brain of individuals with a history of repetitive brain trauma. Lastly, in collaboration with Dr. Nilsson, a leader in the field of amyloid ligands, we will synthesize, identify and characterize 3R and 4R tau-specific ligands. These ligands will be validated using brain tissues of individuals with 3R and 4R tauopathies and working with the Jiang lab we will attempt to determine the corresponding binding site by cryo-EM.

最近，通过首次描述阿尔茨海默病 (AD) 大脑中 tau 蛋白丝的原子结构，在了解 tau 蛋白病以及 tau 蛋白聚集如何导致神经变性方面取得了重大进展。通过我们印第安纳大学实验室和 MRC 分子生物学实验室之间的持续合作，通过冷冻电子显微镜 (cryo-EM) 确定了从 AD 患者大脑中纯化的成对螺旋丝 (PHF) 和直​​丝 (SF) 核心的原子模型。本 MPI 申请中提出的研究是这项开创性工作的逻辑延续。这些研究是对 RFA-NS-18-015“阿尔茨海默病相关痴呆 (ADRD) 蛋白质病的结构生物学”(U01) 的回应。我们的提案有 3 个具体目标。第一个是在印第安纳大学 Vidal 和 Ghetti 实验室以及普渡大学 Jiang 实验室的合作下，生成冷冻电镜图并确定患有散发性和遗传性 3R 和 4R tau蛋白病的个体大脑中 tau 蛋白丝的相应原子模型。重要的是，我们的努力将得到 MRC 合作者 Drs. 的全力支持。戈德特和舍雷斯。其次，我们将生成冷冻电镜图，并确定有重复性脑外伤史的个体大脑中 tau 蛋白丝的相应原子模型。最后，我们将与淀粉样蛋白配体领域的领导者 Nilsson 博士合作，合成、鉴定和表征 3R 和 4R tau 特异性配体。这些配体将使用 3R 和 4R tau蛋白病个体的脑组织进行验证，并与 Jiang 实验室合作，尝试通过冷冻电镜确定相应的结合位点。

项目成果

Thiophene-Based Optical Ligands That Selectively Detect Aβ Pathology in Alzheimer's Disease.

• DOI: 10.1002/cbic.202100199
• 发表时间: 2021-08-03
• 期刊: Chembiochem : a European journal of chemical biology
• 作者: Klingstedt T;Shirani H;Ghetti B;Vidal R;R Nilsson KP
• 通讯作者: R Nilsson KP

TAF15 amyloid filaments in frontotemporal lobar degeneration.

• DOI: 10.1038/s41586-023-06801-2
• 发表时间: 2024-01
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Tetter, Stephan;Arseni, Diana;Murzin, Alexey G.;Buhidma, Yazead;Peak-Chew, Sew Y.;Garringer, Holly J.;Newell, Kathy L.;Vidal, Ruben;Apostolova, Liana G.;Lashley, Tammaryn;Ghetti, Bernardino;Ryskeldi-Falcon, Benjamin
• 通讯作者: Ryskeldi-Falcon, Benjamin

MBIR: A cryo-ET 3D reconstruction method that effectively minimizes missing wedge artifacts and restores missing information.

MBIR：一种冷冻 ET 3D 重建方法，可有效最大限度地减少丢失的楔形伪影并恢复丢失的信息。

• DOI: 10.1016/j.jsb.2019.03.002
• 发表时间: 2019
• 期刊: Journal of structural biology
• 影响因子: 3
• 作者: Yan,Rui;Venkatakrishnan,SinganallurV;Liu,Jun;Bouman,CharlesA;Jiang,Wen
• 通讯作者: Jiang,Wen

Thiophene-Based Ligands for Histological Multiplex Spectral Detection of Distinct Protein Aggregates in Alzheimer's Disease.

用于阿尔茨海默病中不同蛋白质聚集体的组织学多重光谱检测的基于噻吩的配体。

• DOI: 10.1002/chem.202203568
• 发表时间: 2023
• 期刊: Chemistry (Weinheim an der Bergstrasse, Germany)
• 作者: Lantz,Linda;Shirani,Hamid;Ghetti,Bernardino;Vidal,Ruben;Klingstedt,Therése;Nilsson,KPeterR
• 通讯作者: Nilsson,KPeterR

Proteophenes - Amino Acid Functionalized Thiophene-based Fluorescent Ligands for Visualization of Protein Deposits in Tissue Sections with Alzheimer's Disease Pathology.

• DOI: 10.1002/chem.202201557
• 发表时间: 2022-11-07
• 期刊: CHEMISTRY-A EUROPEAN JOURNAL
• 影响因子: 4.3
• 作者: Bjork, Linnea;Back, Marcus;Lantz, Linda;Ghetti, Bernardino;Vidal, Ruben;Klingstedt, Therese;Nilsson, K. Peter R.
• 通讯作者: Nilsson, K. Peter R.