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)脑中tau丝的原子结构，在理解tauopathy以及tau聚集体如何导致神经变性方面取得了重大进展。我们印第安纳大学的实验室和MRC分子生物学实验室正在进行的合作中，用冷冻电子显微镜(Cryo-EM)确定了从AD患者的大脑中纯化的成对螺旋丝(PHF)和直丝(SFS)的核心原子模型。本MPI申请中提出的研究是这一开创性工作的合乎逻辑的延续。这些研究是对RFA-NS-18-015《阿尔茨海默病相关痴呆(ADRD)蛋白病的结构生物学》(U01)的响应。我们的建议有三个具体目标。首先是在印第安纳大学的维达尔和盖蒂实验室以及普渡大学的江实验室的合作下，生成冷冻-EM图，并从患有散发性和遗传性3R和4R tauopathy的个体的大脑中确定相应的tau细丝的原子模型。重要的是，我们的努力将得到MRC合作者Goedert博士和Scheres博士的全力支持。其次，我们将生成一张冷冻-EM图，并从有重复脑损伤史的个人的大脑中确定相应的tau丝的原子模型。最后，我们将与淀粉样蛋白配体领域的领导者尼尔森博士合作，合成、鉴定和表征3R和4R tau特异性配体。这些配体将通过3R和4R紧张症患者的脑组织进行验证，并将与江实验室合作，尝试通过冷冻-EM确定相应的结合位点。

项目成果

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

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

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.