Brown Christine K, Frost Matthew P, Holec Sara A M, Seeley William W, Grinberg Lea T, Olson Steven H, Woerman Amanda L
Department of Biology and Institute for Applied Life Sciences, University of Massachusetts Amherst, Amherst, MA, USA.
Department of Biology and Institute for Applied Life Sciences, University of Massachusetts Amherst, Amherst, MA, USA; Department of Microbiology, Immunology, and Pathology, Prion Research Center, Colorado State University, Fort Collins, CO, USA.
Neurobiol Dis. 2025 Oct 1;214:107052. doi: 10.1016/j.nbd.2025.107052. Epub 2025 Aug 6.
Tauopathies are a group of neurodegenerative diseases caused by misfolding of the protein tau into a β-sheet rich conformation. By inducing misfolding of additional tau monomers, these pathogenic fibrils replicate and spread progressive disease throughout the brain. While frontotemporal lobar degenerative diseases (FTLDs) - including argyrophilic grain disease, corticobasal degeneration, globular glial tauopathy, and progressive supranuclear palsy - are caused by this same underlying molecular process, each disease is defined by a unique clinical and neuropathological presentation. This phenomenon is explained by the strain hypothesis, which proposes that the conformation tau misfolds into determines which disease a patient will develop. Indeed, robust structural and biological data indicate that tau misfolds into conformational arrangements specific to each disease. While these findings are highly impactful for understanding similarities and differences between tauopathies, they have yet to be harnessed to develop a definitive ante-mortem diagnostic. Working toward the goal of disease-specific diagnostics, we created a panel of tau bioreporter cell lines expressing a fragment of human tau fused to yellow fluorescent protein (YFP). Using point mutations designed to interfere with tau misfolding into specific conformations, we quantified YFP-positive puncta after incubating cells with tau fibrils from FTLD patient samples to establish a strain-specific profile for each tauopathy. Not only can we use this approach to differentiate between human tau strains, but we also show that the tau strain found in a commonly used mouse model exhibits properties that significantly differ from those seen in human patients.
tau蛋白病是一组神经退行性疾病，由蛋白质tau错误折叠成富含β-折叠的构象引起。通过诱导额外的tau单体错误折叠，这些致病性纤维会复制并在整个大脑中传播进行性疾病。虽然额颞叶变性疾病（FTLDs）——包括嗜银颗粒病、皮质基底节变性、球状胶质tau蛋白病和进行性核上性麻痹——是由相同的潜在分子过程引起的，但每种疾病都由独特的临床和神经病理学表现来定义。这种现象可以用毒株假说来解释，该假说提出tau蛋白错误折叠形成的构象决定了患者会患哪种疾病。确实，有力的结构和生物学数据表明，tau蛋白会错误折叠成每种疾病特有的构象排列。虽然这些发现对于理解tau蛋白病之间的异同具有高度影响力，但它们尚未被用于开发明确的生前诊断方法。为了实现疾病特异性诊断的目标，我们创建了一组tau生物报告细胞系，这些细胞系表达与黄色荧光蛋白（YFP）融合的人tau片段。通过设计点突变来干扰tau蛋白错误折叠成特定构象，我们在用来自FTLD患者样本的tau纤维孵育细胞后，对YFP阳性斑点进行了定量，以建立每种tau蛋白病的毒株特异性图谱。我们不仅可以使用这种方法区分人tau毒株，而且还表明在常用小鼠模型中发现的tau毒株表现出与人类患者显著不同的特性。
