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

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish (US)
Article number12185
JournalNature Communications
Volume7
DOIs
StatePublished - Jul 15 2016

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endoplasmic reticulum
homeostasis
Tuberous Sclerosis
Oligodendroglia
Homeostasis
myelin
deletion
phosphatases
defects
abnormalities
Guanabenz
mutations
death
ablation
mice
Defects
Endoplasmic Reticulum Stress
activation
Cell death
Ablation

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Regulation of PERK-eIF2α signalling by tuberous sclerosis complex-1 controls homoeostasis and survival of myelinating oligodendrocytes. / Jiang, Minqing; Liu, Lei; He, Xuelian; Wang, Haibo; Lin, Wensheng; Wang, Huimin; Yoon, Sung O.; Wood, Teresa L.; Lu, Q. Richard.

In: Nature Communications, Vol. 7, 12185, 15.07.2016.

Research output: Contribution to journalArticle

Jiang, Minqing ; Liu, Lei ; He, Xuelian ; Wang, Haibo ; Lin, Wensheng ; Wang, Huimin ; Yoon, Sung O. ; Wood, Teresa L. ; Lu, Q. Richard. / Regulation of PERK-eIF2α signalling by tuberous sclerosis complex-1 controls homoeostasis and survival of myelinating oligodendrocytes. In: Nature Communications. 2016 ; Vol. 7.
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