Regulation of PERK-eIF2alpha Signaling by Tuberous Sclerosis Complex-1 Controls Homeostasis and Survival of Myelinating Oligodendrocytes

Tuberous sclerosis complex (TSC), an autosomal dominant disorder caused by mutations in either TSC1 or TSC2, exhibits white matter abnormalities including CNS myelin deficits. however, underlying mechanisms are not fully understood. Here we find that, unexpectedly, constitutive activation of mTOR signaling caused by Tsc1 deletion in the oligodendrocyte lineage results in severe myelination defects and oligodendrocyte cell death. Expression profiling analysis reveals that Tsc1 ablation induces prominent endoplasmic reticulum (ER) stress responses through the PERK-eIF2alpha dependent signaling axis and activates Fas-JNK apoptotic pathways. Our studies suggest that TSC1-mTOR signaling acts as an important checkpoint for maintaining oligodendrocyte homeostasis. Gene expression profiling of optic nerve from P12 control and Tsc1cKO mice结节性硬化复合体（TSC）是一种由TSC1或TSC2基因突变引发的常染色体显性遗传病，可表现出包括中枢神经系统（Central Nervous System, CNS）髓磷脂缺陷在内的白质异常，但其潜在发病机制尚未完全阐明。本研究意外发现，少突胶质细胞谱系中Tsc1缺失所导致的哺乳动物雷帕霉素靶蛋白（mTOR）信号通路持续性激活，会引发严重的髓鞘形成缺陷与少突胶质细胞死亡。表达谱分析显示，Tsc1敲除会通过PERK-eIF2α依赖的信号轴诱导显著的内质网（ER）应激反应，并激活Fas-JNK凋亡通路。本研究表明，TSC1-mTOR信号通路是维持少突胶质细胞稳态的重要检查点。本研究还对出生后12天（P12）对照组与Tsc1条件性敲除（Tsc1cKO）小鼠的视神经进行了基因表达谱分析。