Clinical progression of tauopathies is reflected by the transcellular propagation of pathogenic Tau seeds with the possible involvement of extracellular vesicles as transport vectors. However, the mechanism regulating extracellular vesicle cargo delivery to recipient cells is poorly understood. We established a cell model for investigating extracellular vesicle-delivery of membranes and proteins. In this model, extracellular vesicles are readily internalized and accumulate in endolysosomes. For the first time, we show that in this acidic compartment of recipient cells, extracellular vesicle-delivered Tau seeds cause the accumulation and abnormal folding of normal Tau by a process that requires the participation of autophagy. Endolysomes represent thus a cross-road where Tau seeds released from extracellular vesicles propagate on cellular Tau on its route for autophagy-mediated degradation, ultimately driving its accumulation, endolysosomal stress and cytotoxicity. Whilst, autophagy stimulation is considered as a viable solution to protect neurons from harmful cytosolic protein inclusions, our data suggest that this approach may favour the aberrant accumulation of neurodegeneration-associated proteins induced by exogenous pathogenic protein forms, with possible implications in the spreading of the disease.

中文翻译：

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细胞外囊泡劫持自噬途径，以诱导Tau在内涵体中的积累。

tauopathies的临床进展通过病原性Tau种子的跨细胞传播反映出来，并可能以细胞外囊泡为转运载体。但是，调节细胞外小泡货物输送到受体细胞的机制了解甚少。我们建立了一个细胞模型，用于研究细胞外膜和蛋白质的囊泡传递。在该模型中，细胞外囊泡很容易被内在化并蓄积在溶酶体中。首次，我们显示在受体细胞的这个酸性隔室中，细胞外囊泡输送的Tau种子通过需要自噬参与的过程引起正常Tau的积累和异常折叠。因此，内溶体代表了一个十字路口，其中从细胞外囊泡释放的Tau种子在细胞Tau上进行自噬介导的降解，最终驱动其积累，溶酶体应激和细胞毒性。虽然自噬刺激被认为是保护神经元免受有害胞质蛋白质包涵的可行解决方案，但我们的数据表明，这种方法可能有利于外源性致病蛋白形式诱导的神经退行性相关蛋白的异常积累，并可能影响其的扩散。疾病。