Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104.
Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Proc Natl Acad Sci U S A. 2021 May 11;118(19). doi: 10.1073/pnas.2021461118.
Tau is a microtubule-associated protein, which promotes neuronal microtubule assembly and stability. Accumulation of tau into insoluble aggregates known as neurofibrillary tangles (NFTs) is a pathological hallmark of several neurodegenerative diseases. The current hypothesis is that small, soluble oligomeric tau species preceding NFT formation cause toxicity. However, thus far, visualizing the spatial distribution of tau monomers and oligomers inside cells under physiological or pathological conditions has not been possible. Here, using single-molecule localization microscopy, we show that tau forms small oligomers on microtubules ex vivo. These oligomers are distinct from those found in cells exhibiting tau aggregation and could be precursors of aggregated tau in pathology. Furthermore, using an unsupervised shape classification algorithm that we developed, we show that different tau phosphorylation states are associated with distinct tau aggregate species. Our work elucidates tau's nanoscale composition under nonaggregated and aggregated conditions ex vivo.
tau 是一种微管相关蛋白，可促进神经元微管的组装和稳定性。tau 聚集成不溶性聚集体，即神经原纤维缠结 (NFT)，这是几种神经退行性疾病的病理标志。目前的假设是，NFT 形成之前，tau 以小的可溶性寡聚体形式存在并引起毒性。然而，到目前为止，还无法在生理或病理条件下可视化细胞内 tau 单体和寡聚体的空间分布。在这里，我们使用单分子定位显微镜显示 tau 在微管上形成小的寡聚体。这些寡聚体与在表现出 tau 聚集的细胞中发现的寡聚体不同，可能是病理学中聚集 tau 的前体。此外，我们使用自主开发的无监督形状分类算法，表明 tau 的不同磷酸化状态与不同的 tau 聚集物种有关。我们的工作阐明了 tau 在非聚集和聚集状态下的纳米尺度组成。
