Regulation of PERK–eIF2α signalling by tuberous sclerosis complex-1 controls homoeostasis and survival of myelinating oligodendrocytes

Minqing Jiang, Lei Liu, Xuelian He, Haibo Wang, Wensheng Lin, Huimin Wang, Sung O. Yoon, Teresa L. Wood and Q. Richard Lu ()
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Minqing Jiang: Key Laboratory of Brain Functional Genomics of STCSM, Institute of Cognitive Neuroscience, East China Normal University
Lei Liu: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Second Hospital, Sichuan University
Xuelian He: Cincinnati Children’s Hospital Medical Center, University of Cincinnati
Haibo Wang: Cincinnati Children’s Hospital Medical Center, University of Cincinnati
Wensheng Lin: Institute for Translational Neuroscience, University of Minnesota
Huimin Wang: Key Laboratory of Brain Functional Genomics of STCSM, Institute of Cognitive Neuroscience, East China Normal University
Sung O. Yoon: Center for Molecular Neurobiology, The Ohio State University
Teresa L. Wood: New Jersey Medical School Cancer Center, Rutgers Biomedical and Health Sciences
Q. Richard Lu: Cincinnati Children’s Hospital Medical Center, University of Cincinnati

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12185

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