Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI, 49503, USA.
Neuroscience Program, Michigan State University, East Lansing, MI, 48825, USA.
Nat Commun. 2020 Jun 4;11(1):2809. doi: 10.1038/s41467-020-16580-3.
Formation of membrane-less organelles via liquid-liquid phase separation is one way cells meet the biological requirement for spatiotemporal regulation of cellular components and reactions. Recently, tau, a protein known for its involvement in Alzheimer's disease and other tauopathies, was found to undergo liquid-liquid phase separation making it one of several proteins associated with neurodegenerative diseases to do so. Here, we demonstrate that tau forms dynamic liquid droplets in vitro at physiological protein levels upon molecular crowding in buffers that resemble physiological conditions. Tau droplet formation is significantly enhanced by disease-associated modifications, including the AT8 phospho-epitope and the P301L tau mutation linked to an inherited tauopathy. Moreover, tau droplet dynamics are significantly reduced by these modified forms of tau. Extended phase separation promoted a time-dependent adoption of toxic conformations and oligomerization, but not filamentous aggregation. P301L tau protein showed the greatest oligomer formation following extended phase separation. These findings suggest that phase separation of tau may facilitate the formation of non-filamentous pathogenic tau conformations.
液-液相分离形成无膜细胞器是细胞满足细胞成分和反应时空调节的生物学需求的一种方式。最近，tau 蛋白，一种已知与阿尔茨海默病和其他 tau 病有关的蛋白质，被发现经历液-液相分离，使其成为与神经退行性疾病相关的几种蛋白质之一。在这里，我们证明 tau 在分子拥挤的生理条件缓冲液中以生理蛋白水平在体外形成动态液滴。tau 液滴的形成通过疾病相关的修饰显著增强，包括与遗传性 tau 病相关的 AT8 磷酸化表位和 P301L tau 突变。此外，tau 液滴的动力学通过这些修饰形式的 tau 显著降低。扩展的相分离促进了有毒构象和寡聚化的时间依赖性形成，但不形成丝状聚集。经过扩展的相分离后，P301L tau 蛋白表现出最大的寡聚体形成。这些发现表明 tau 的相分离可能有助于形成非丝状致病性 tau 构象。
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