Closing the gap between structural biology and translational science for amyloid diseases

项目摘要/摘要 最近对淀粉样纤维的冷冻电子显微镜(Cryo-EM)研究浪潮突显了这种复杂性 淀粉样变性疾病患者中蛋白质沉积的研究。在微管tau中发现了一个令人信服的例子。 一种结合蛋白，其病理性聚集会导致肌萎缩侧索硬化。这些变态中的每一个似乎都是 与特定的结构组合相关的，暗示因果关系。类似于tauopy病，其他淀粉样蛋白 疾病表现出不同的预后、发病和症状。这就是TDP-43，α-突触核蛋白， β-淀粉样蛋白，或转甲状腺素(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件，类似于在tau中发现的。因此，检测到 及时发现这些疾病的特异性组合可以确保适当的诊断和治疗。 我们的目标是在淀粉样病模型中使用冷冻-EM和一种联合成像技术绘制淀粉样蛋白纤维的结构图谱。 培养系统将在我们实验室开发。利用获得的结构信息，我们的实验室将 设计结构特异性多肽，用于检测和抑制细胞、小鼠和患者中的淀粉样纤维。 派生样本。如果成功，我们的研究将成为个性化发展的启动平台 淀粉样变性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.