Regulation of PERK-eIF2α signalling by tuberous sclerosis complex-1 controls homoeostasis and survival of myelinating oligodendrocytes.
Regulation of PERK-eIF2α signalling by tuberous sclerosis complex-1 controls homoeostasis and survival of myelinating oligodendrocytes.
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结节硬化症复合物对PERK-EIF2α信号传导的调节控制同性恋和髓生成少突胶质细胞的存活。
DOI：
10.1038/ncomms12185
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发表时间：
2016-07-15
影响因子：
16.6
通讯作者：
Lu QR
中科院分区：
文献类型：
--
作者：
Jiang M;Liu L;He X;Wang H;Lin W;Wang H;Yoon SO;Wood TL;Lu QR
结节性硬化症复合体1或2 （TSC1/2）突变导致白质异常，包括中枢神经系统髓磷脂缺陷；然而，潜在的机制尚不完全清楚。TSC1/2负向调节mTOR的功能，而mTOR是少突胶质细胞分化所必需的。在这里，我们报告，出乎意料的是，在小鼠少突胶质细胞谱系中，通过Tsc1缺失mTOR信号的组成性激活导致严重的髓鞘形成缺陷和少突胶质细胞死亡，尽管在早期发育过程中少突胶质细胞前体最初增加。表达谱分析显示，Tsc1消融通过激活PERK-eIF2α信号轴和Fas-JNK凋亡通路，诱导显著的内质网（ER）应激反应。guanabenz抑制Gadd34-PP1磷酸酶增强磷酸化- eif2 α适应途径，保护少突胶质细胞，部分修复Tsc1突变体的髓鞘形成缺陷。因此，TSC1-mTOR信号作为维持少突胶质细胞稳态的重要检查点，指出了一种以前未被表征的内质网应激机制，该机制有助于结节性硬化症的髓鞘化降低。调控髓鞘形成的分子机制仅被部分理解。本文作者表明，在小鼠少突胶质细胞谱系中，Tsc1的消融激活了内质网应激和凋亡程序，并且增强PERK-eIF2α信号传导部分地挽救了Tsc1突变体的髓鞘形成缺陷。
Tuberous sclerosis complex-1 or 2 (TSC1/2) mutations cause white matter abnormalities, including myelin deficits in the CNS; however, underlying mechanisms are not fully understood. TSC1/2 negatively regulate the function of mTOR, which is required for oligodendrocyte differentiation. Here we report that, unexpectedly, constitutive activation of mTOR signalling by Tsc1 deletion in the oligodendrocyte lineage results in severe myelination defects and oligodendrocyte cell death in mice, despite an initial increase of oligodendrocyte precursors during early development. Expression profiling analysis reveals that Tsc1 ablation induces prominent endoplasmic reticulum (ER) stress responses by activating a PERK–eIF2α signalling axis and Fas–JNK apoptotic pathways. Enhancement of the phospho-eIF2α adaptation pathway by inhibition of Gadd34-PP1 phosphatase with guanabenz protects oligodendrocytes and partially rescues myelination defects in Tsc1 mutants. Thus, TSC1-mTOR signalling acts as an important checkpoint for maintaining oligodendrocyte homoeostasis, pointing to a previously uncharacterized ER stress mechanism that contributes to hypomyelination in tuberous sclerosis. The molecular mechanisms regulating myelination are only partially understood. Here authors show that Tsc1 ablation in oligodendrocyte lineage activates ER stress and apoptotic programs in mice, and that enhancing PERK-eIF2α signalling partially rescues the myelination defects in Tsc1 mutants.