Atomic models of human tau filaments and development of tau ligands

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。

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.