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, Q. Richard Lu

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34 Scopus citations


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.

Original languageEnglish (US)
Article number12185
JournalNature communications
StatePublished - Jul 15 2016

Bibliographical note

Funding Information:
This study was funded in part by grants from the US National Institutes of Health R01NS072427 and R01NS075243 to Q.R.L., NS082203 to T.L.W., the National Multiple Sclerosis Society (RG 5332) to Q.R.L. and National Natural Science Foundation of China NSFC 31271134 to Hu.W.


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