Misfolded, pathological Tau protein propagates from cell to cell causing neuronal degeneration in Alzheimer's disease and other tauopathies. The molecular mechanisms of this process have remained elusive. Unconventional secretion of Tau takes place via several different routes, including direct penetration through the plasma membrane. Here, we show that Tau secretion requires membrane interaction via disulphide bridge formation. Mutating residues that reduce Tau interaction with membranes or formation of disulphide bridges decrease both Tau secretion from cells, and penetration through artificial lipid membranes. Our results demonstrate that Tau is indeed able to penetrate protein-free membranes in a process independent of active cellular processes and that both membrane interaction and disulphide bridge formation are needed for this process. QUARK-based de novo modelling of the second and third microtubule-binding repeat domains, in which the two cysteine residues of 4R isoforms of Tau are located, supports the concept that this region of Tau could form transient amphipathic helices for membrane interaction.

中文翻译：

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Tau 非常规分泌中的膜相互作用和二硫键形成。

错误折叠的病理性 Tau 蛋白从一个细胞传播到另一个细胞，导致阿尔茨海默病和其他 tau 病变中的神经元变性。这一过程的分子机制仍然难以捉摸。Tau 的非常规分泌通过几种不同的途径发生，包括直接穿透质膜。在这里，我们表明 Tau 分泌需要通过二硫键形成的膜相互作用。减少 Tau 与膜的相互作用或二硫键形成的突变残基会减少细胞的 Tau 分泌和通过人造脂质膜的渗透。我们的研究结果表明，Tau 确实能够在一个独立于活性细胞过程的过程中穿透不含蛋白质的膜，并且该过程需要膜相互作用和二硫键形成。