Department of Neuroscience, Institute of Neurosurgery, and Department of Neurosurgery, The First Affiliated Hospital, State Key Laboratory of Cellular Stress Biology, School of Medicine.
Xiamen Key Laboratory of Brain Center, The First Affiliated Hospital.
J Clin Invest. 2022 Apr 1;132(7). doi: 10.1172/JCI155096.
Dysfunction of protein trafficking has been intensively associated with neurological diseases, including neurodegeneration, but whether and how protein transport contributes to oligodendrocyte (OL) maturation and myelin repair in white matter injury remains unclear. ER-to-Golgi trafficking of newly synthesized proteins is mediated by coat protein complex II (COPII). Here, we demonstrate that the COPII component Sec13 was essential for OL differentiation and postnatal myelination. Ablation of Sec13 in the OL lineage prevented OPC differentiation and inhibited myelination and remyelination after demyelinating injury in the central nervous system (CNS), while improving protein trafficking by tauroursodeoxycholic acid (TUDCA) or ectopic expression of COPII components accelerated myelination. COPII components were upregulated in OL lineage cells after demyelinating injury. Loss of Sec13 altered the secretome of OLs and inhibited the secretion of pleiotrophin (PTN), which was found to function as an autocrine factor to promote OL differentiation and myelin repair. These data suggest that Sec13-dependent protein transport is essential for OL differentiation and that Sec13-mediated PTN autocrine signaling is required for proper myelination and remyelination.
蛋白质运输功能障碍与包括神经退行性疾病在内的多种神经疾病密切相关，但蛋白质运输是否以及如何促进白质损伤中的少突胶质细胞（OL）成熟和髓鞘修复仍不清楚。内质网到高尔基体的新合成蛋白运输是由衣被蛋白复合物 II（COPII）介导的。在这里，我们证明了 COPII 成分 Sec13 对于 OL 分化和出生后髓鞘形成是必不可少的。在中枢神经系统（CNS）脱髓鞘损伤后，OL 谱系中 Sec13 的缺失阻止了少突胶质前体细胞分化，并抑制了髓鞘形成和髓鞘再生，而通过牛磺熊脱氧胆酸（TUDCA）或 COPII 成分的异位表达来改善蛋白质运输则加速了髓鞘形成。COPII 成分在脱髓鞘损伤后的 OL 谱系细胞中上调。Sec13 的缺失改变了 OL 的分泌组，并抑制了多效蛋白（PTN）的分泌，发现 PTN 作为一种自分泌因子，可促进 OL 分化和髓鞘修复。这些数据表明，Sec13 依赖性蛋白质运输对于 OL 分化是必不可少的，并且 Sec13 介导的 PTN 自分泌信号对于适当的髓鞘形成和髓鞘再生是必需的。
