Angera Isaac J, Xu Xueyong, Rajewski Benjamin H, Hallinan Grace I, Zhang Xiaoqi, Ghetti Bernardino, Vidal Ruben, Jiang Wen, Del Valle Juan R
Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame, IN, USA.
Department of Biological Sciences, Purdue University, West Lafayette, IN, USA.
Nat Chem. 2025 Apr 30. doi: 10.1038/s41557-025-01805-z.
Tauopathies are a class of neurodegenerative disorders that feature tau protein aggregates in the brain. Misfolded tau has the capacity to seed the fibrillization of soluble tau, leading to the prion-like spread of aggregates. Within these filaments, tau protomers always exhibit a cross-β amyloid structure. However, distinct cross-β amyloid folds correlate with specific diseases. An understanding of how these conformations impact seeding activity remains elusive. Identifying the minimal epitopes required for transcellular propagation of tau aggregates represents a key step towards more relevant models of disease progression. Here we implement a diversity-oriented peptide macrocyclization approach towards miniature tau, or 'mini-tau', proteomimetics that can seed the aggregation of tau in engineered cells and primary neurons. Structural elucidation of one such seed-competent macrocycle reveals remarkable conformational congruence with core folds from patient-derived extracts of tau. The ability to impart β-arch form and function through peptide stapling has broad-ranging implications for the minimization and mimicry of pathological tau and other amyloid proteins that drive neurodegeneration.
tau蛋白病是一类神经退行性疾病，其特征是大脑中存在tau蛋白聚集体。错误折叠的tau蛋白能够引发可溶性tau蛋白的纤维化，导致聚集体像朊病毒一样传播。在这些细丝中，tau原纤维总是呈现出交叉β淀粉样结构。然而，不同的交叉β淀粉样折叠与特定疾病相关。目前尚不清楚这些构象如何影响种子活性。确定tau聚集体跨细胞传播所需的最小表位是建立更相关疾病进展模型的关键一步。在这里，我们对微型tau或“迷你tau”蛋白质模拟物采用了一种面向多样性的肽大环化方法，这种模拟物能够在工程细胞和原代神经元中引发tau蛋白的聚集。对一种具有种子活性的大环化合物的结构解析表明，它与来自患者tau提取物的核心折叠具有显著的构象一致性。通过肽链订书作用赋予β-拱结构和功能的能力，对于最小化和模拟驱动神经退行性变的病理性tau蛋白和其他淀粉样蛋白具有广泛的意义。
