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

Nat Commun. 2016 Jul 15;7:12185. doi: 10.1038/ncomms12185.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / genetics
  • Cell Survival
  • Female
  • Guanabenz / pharmacology
  • Homeostasis
  • Male
  • Mice, Knockout
  • Myelin Sheath / metabolism
  • Oligodendroglia / cytology
  • Oligodendroglia / drug effects
  • Oligodendroglia / metabolism*
  • Protein Phosphatase 1 / metabolism
  • Protein-Serine-Threonine Kinases / metabolism*
  • Rats
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism
  • Tuberous Sclerosis Complex 1 Protein
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • eIF-2 Kinase / metabolism*

Substances

  • Tsc1 protein, mouse
  • Tsc1 protein, rat
  • Tuberous Sclerosis Complex 1 Protein
  • Tumor Suppressor Proteins
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • PERK kinase
  • Protein-Serine-Threonine Kinases
  • eIF-2 Kinase
  • eIF2alpha kinase, mouse
  • Ppp1r15a protein, mouse
  • Protein Phosphatase 1
  • Guanabenz