Atomic models of human tau filaments and development of tau ligands

最近，通过首次描述来自阿尔茨海默病（AD）大脑的tau纤维的原子结构，在理解tau病变和tau聚集体如何导致神经退行性变方面取得了重大进展。通过我们在印第安纳大学的实验室和MRC分子生物学实验室的持续合作，通过冷冻电子显微镜（cro - em）确定了从AD患者的大脑中纯化的成对螺旋丝（phf）和直丝（sf）核心的原子模型。在这个MPI应用中提出的研究是这个开创性工作的逻辑延续。这些研究是响应RFA-NS-18-015“阿尔茨海默病相关痴呆（ADRDs）蛋白病变的结构生物学”（U01）。我们的建议有三个具体目标。首先是在印第安纳大学的Vidal和Ghetti实验室以及普渡大学的Jiang实验室的合作下，生成一个低温电子显微镜图谱，并确定来自散发性和遗传性3R和4R tau病变个体大脑中tau蛋白细丝的相应原子模型。重要的是，我们的努力将得到我们在MRC的合作者的全力支持。Goedert和Scheres。其次，我们将生成一个低温电镜图，并从具有重复性脑外伤史的个体的大脑中确定相应的tau丝的原子模型。最后，与淀粉样体配体领域的领导者Nilsson博士合作，我们将合成，鉴定和表征3R和4R tau特异性配体。这些配体将使用患有3R和4R tau病变的个体的脑组织进行验证，并与Jiang实验室合作，我们将尝试通过冷冻电镜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.