Closing the gap between structural biology and translational science for amyloid

项目总结/摘要 最近一波对淀粉样纤维的冷冻电子显微镜（cryo-EM）研究突出了淀粉样纤维的复杂性， 淀粉样疾病患者的蛋白质沉积。一个令人信服的例子是在tau蛋白中发现的， 病理性聚集引起tau蛋白病的结合蛋白。每一种tau蛋白病 与一个特定的结构组合有关，表明因果关系。与tau蛋白病相似，其他淀粉样蛋白 疾病表现出不同的预后、发作和症状。这是TDP-43，α-突触核蛋白， β-淀粉样蛋白或甲状腺素运载蛋白（TTR），仅举几例。我们假设这些表型差异是由 通过形成各种结构组装，类似于在tau中发现的。因此，检测 这些疾病特异性组件的及时检测可以确保正确的诊断和治疗。 我们的目的是利用冷冻电镜和共聚焦显微镜， 培养系统，在我们的实验室。利用获得的结构信息，我们的实验室将 设计结构特异性肽，用于检测和抑制细胞、小鼠和患者中的淀粉样蛋白原纤维， 衍生样品。如果成功，我们的研究将作为一个启动平台，为发展个性化 淀粉样蛋白疾病的基于结构的诊断和治疗。

PROJECT SUMMARY/ABSTRACT The recent wave of cryo-electron microscopy (cryo-EM) studies on amyloid fibrils has highlighted the complexity of protein deposition amongst patients of amyloid diseases. A convincing example is found in tau, a microtubule binding protein whose pathological aggregation causes tauopathies. Each of these tauopathies seems to be associated with a particular structural assembly, suggesting causality. Similar to tauopathies, other amyloid diseases manifest differential prognosis, onset, and symptomatology. This is the case of TDP-43, α-synuclein, β-amyloid, or transthyretin (TTR), to name a few. We hypothesize that these phenotypical differences are driven by the formation of various structural assemblies, similar to what is found in tau. As a consequence, the detection of these disease-specific assemblies in a timely manner could ensure proper diagnosis and treatment. We aim to map the structural spectrum of amyloid fibrils in an amyloid disease model using cryo-EM and a co- culture system to be developed in our laboratory. Using the obtained structural information, our laboratory will design structure-specific peptides for the detection and inhibition of amyloid fibrils in cells, mice, and patient- derived samples. If successful, our study will serve as a launching platform for the development of personalized structure-based diagnostics and therapeutics for amyloid diseases.