Biomolecular condensation of the neuronal microtubule-associated protein Tau (MAPT) can be induced by coacervation with polyanions like RNA, or by molecular crowding. Tau condensates have been linked to both functional microtubule binding and pathological aggregation in neurodegenerative diseases. We find that molecular crowding and coacervation with RNA, two conditions likely coexisting in the cytosol, synergize to enable Tau condensation at physiological buffer conditions and to produce condensates with a strong affinity to charged surfaces. During condensate-mediated microtubule polymerization, their synergy enhances bundling and spatial arrangement of microtubules. We further show that different Tau condensates efficiently induce pathological Tau aggregates in cells, including accumulations at the nuclear envelope that correlate with nucleocytoplasmic transport deficits. Fluorescent lifetime imaging reveals different molecular packing densities of Tau in cellular accumulations and a condensate-like density for nuclear-envelope Tau. These findings suggest that a complex interplay between interaction partners, post-translational modifications, and molecular crowding regulates the formation and function of Tau condensates. Conditions leading to prolonged existence of Tau condensates may induce the formation of seeding-competent Tau and lead to distinct cellular Tau accumulations.

中文翻译：

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分子拥挤和 RNA 协同促进相分离、微管相互作用和 Tau 凝聚物的接种。


神经元微管相关蛋白 Tau (MAPT) 的生物分子凝聚可以通过与 RNA 等聚阴离子凝聚或通过分子拥挤来诱导。 Tau 蛋白凝聚物与神经退行性疾病中的功能性微管结合和病理性聚集有关。我们发现分子拥挤和与 RNA 的凝聚这两种可能共存于细胞质中的条件协同作用，使 Tau 在生理缓冲条件下凝结，并产生对带电表面具有强亲和力的凝结物。在冷凝介导的微管聚合过程中，它们的协同作用增强了微管的成束和空间排列。我们进一步表明，不同的 Tau 凝聚物可有效诱导细胞中的病理性 Tau 聚集，包括与核细胞质运输缺陷相关的核膜处的积累。荧光寿命成像揭示了细胞积累中 Tau 的不同分子堆积密度以及核膜 Tau 的凝结样密度。这些发现表明，相互作用伙伴、翻译后修饰和分子拥挤之间复杂的相互作用调节 Tau 缩合物的形成和功能。导致 Tau 凝聚物长期存在的条件可能会诱导具有播种能力的 Tau 的形成，并导致明显的细胞 Tau 积累。