MRC Laboratory of Molecular Biology, Cambridge, UK.
MRC Laboratory of Molecular Biology, Cambridge, UK
EMBO J. 2018 Mar 15;37(6). doi: 10.15252/embj.201797822. Epub 2018 Mar 1.
Protein aggregation is a hallmark of diverse neurodegenerative diseases. Multiple lines of evidence have revealed that protein aggregates can penetrate inside cells and spread like prions. How such aggregates enter cells remains elusive. Through a focused siRNA screen targeting genes involved in membrane trafficking, we discovered that mutant SOD1 aggregates, like viruses, exploit cofilin-1 to remodel cortical actin and enter cells. Upstream of cofilin-1, signalling from the RHO GTPase and the ROCK1 and LIMK1 kinases controls cofilin-1 activity to remodel actin and modulate aggregate entry. In the spinal cord of symptomatic SOD1 transgenic mice, cofilin-1 phosphorylation is increased and actin dynamics altered. Importantly, the RHO to cofilin-1 signalling pathway also modulates entry of tau and α-synuclein aggregates. Our results identify a common host cell signalling pathway that diverse protein aggregates exploit to remodel actin and enter cells.
蛋白质聚集是多种神经退行性疾病的一个标志。多条证据表明，蛋白质聚集体可以穿透细胞内部并像朊病毒一样传播。然而，这些聚集体如何进入细胞仍然是个谜。通过针对涉及膜运输的基因的靶向 siRNA 筛选，我们发现突变型 SOD1 聚集体像病毒一样利用肌动蛋白丝切割蛋白 1 来重塑皮质肌动蛋白并进入细胞。在肌动蛋白丝切割蛋白 1 的上游，RHO GTPase 和 ROCK1、LIMK1 激酶的信号传导控制肌动蛋白丝切割蛋白 1 的活性，以重塑肌动蛋白并调节聚集体的进入。在有症状的 SOD1 转基因小鼠的脊髓中，肌动蛋白丝切割蛋白 1 的磷酸化增加，肌动蛋白动力学发生改变。重要的是，RHO 到肌动蛋白丝切割蛋白 1 的信号通路也调节 tau 和 α-突触核蛋白聚集体的进入。我们的结果确定了一种常见的宿主细胞信号通路，多种蛋白质聚集体利用该信号通路来重塑肌动蛋白并进入细胞。
