Abstract
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.
Highlights
Tuberous sclerosis complex-1 or 2 (TSC1/2) mutations cause white matter abnormalities, including myelin deficits in the central nervous system (CNS); underlying mechanisms are not fully understood
Western blot analysis indicated that the levels of Tsc[1] and Tsc[2] decreased gradually as OL precursor (OPC) matured, both proteins were expressed on all OL lineage cells to some extent (Fig. 1b)
Treatment with FasL significantly increased the percentage of OPCs that underwent cell death (Fig. 6f,g), indicating that the Fas activation triggers apoptotic signalling to cause OL cell death. These results suggest that sustained hyperactivation of mTOR caused by Tsc[1] ablation activates the apoptotic pathway during the onset of OPC differentiation
Summary
Tuberous sclerosis complex-1 or 2 (TSC1/2) mutations cause white matter abnormalities, including myelin deficits in the CNS; underlying mechanisms are not fully understood. In response to ER stress, an adaptive program known as the integrated stress response is activated This stress response can be mediated by the pancreatic ER kinase (PERK), which phosphorylates eukaryotic translation initiation factor 2a (p-eIF2a) to attenuate global protein synthesis and ER stress to maintain proteostasis[20]. This process upregulates transcription factors, such as ATF4, that activate cytoprotective responses and C/EBP-homologous protein (CHOP) expression[19,21], while accumulation of CHOP can induce apoptosis[22]
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