Neuroscience Center, HiLIFE, University of Helsinki, Helsinki 00014, Finland.
Biosci Rep. 2021 Aug 27;41(8). doi: 10.1042/BSR20210148.
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 (MTBDs), 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.
错误折叠的病理性 tau 蛋白在阿尔茨海默病和其他 tau 病中从一个细胞传播到另一个细胞，导致神经元变性。这个过程的分子机制一直难以捉摸。tau 的非常规分泌通过几种不同的途径进行，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进行膜相互作用。突变降低 tau 与膜相互作用或二硫键形成的残基会减少 tau 从细胞中的分泌以及穿透人工脂质膜。我们的结果表明，tau 确实能够在不依赖于主动细胞过程的情况下穿透无蛋白质的膜，并且膜相互作用和二硫键形成对于该过程都是必需的。基于 QUARK 的 tau 的第二个和第三个微管结合重复结构域（MTBD）的从头建模，其中包含 4R 同工型 tau 的两个半胱氨酸残基，支持了这一观点，即 tau 的这一区域可以形成用于膜相互作用的瞬时两亲性螺旋。
