Tau forms oligomeric complexes on microtubules that are distinct from tau aggregates
Tau forms oligomeric complexes on microtubules that are distinct from tau aggregates
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DOI：
10.1073/pnas.2021461118
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发表时间：
2021-05-11
影响因子：
11.1
通讯作者：
Lakadamyali, Melike
中科院分区：
文献类型：
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作者：
Gyparaki, Melina Theoni;Arab, Arian;Lakadamyali, Melike
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堆积成称为神经原纤维缠结(NFTs)的不溶性聚集体，是几种神经退行性疾病的病理特征。目前的假设是，在NFT形成之前，小的、可溶的寡聚体tau物种会产生毒性。然而，到目前为止，还不可能在生理或病理条件下可视化tau单体和寡聚体在细胞内的空间分布。在这里，使用单分子定位显微镜，我们发现tau在体外的微管上形成小的低聚物。这些寡聚体不同于在表现tau聚集的细胞中发现的那些寡聚体，在病理学上可能是聚集tau的前体。此外，使用我们开发的无监督形状分类算法，我们证明了不同的tau磷酸化状态与不同的tau聚集体相关。我们的工作阐明了tau在非聚集和体外聚集条件下的纳米组成。
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.