Gsta4 controls apoptosis of differentiating adult oligodendrocytes during homeostasis and remyelination via the mitochondria-associated Fas-Casp8-Bid-axis

Nat Commun. 2020 Aug 13;11(1):4071. doi: 10.1038/s41467-020-17871-5.


Arrest of oligodendrocyte (OL) differentiation and remyelination following myelin damage in multiple sclerosis (MS) is associated with neurodegeneration and clinical worsening. We show that Glutathione S-transferase 4α (Gsta4) is highly expressed during adult OL differentiation and that Gsta4 loss impairs differentiation into myelinating OLs in vitro. In addition, we identify Gsta4 as a target of both dimethyl fumarate, an existing MS therapy, and clemastine fumarate, a candidate remyelinating agent in MS. Overexpression of Gsta4 reduces expression of Fas and activity of the mitochondria-associated Casp8-Bid-axis in adult oligodendrocyte precursor cells, leading to improved OL survival during differentiation. The Gsta4 effect on apoptosis during adult OL differentiation was corroborated in vivo in both lysolecithin-induced demyelination and experimental autoimmune encephalomyelitis models, where Casp8 activity was reduced in Gsta4-overexpressing OLs. Our results identify Gsta4 as an intrinsic regulator of OL differentiation, survival and remyelination, as well as a potential target for future reparative MS therapies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Apoptosis / physiology
  • Caspase 8 / genetics
  • Caspase 8 / metabolism
  • Cell Differentiation / genetics
  • Cell Differentiation / physiology
  • Cells, Cultured
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Glutathione Transferase / genetics
  • Glutathione Transferase / metabolism*
  • Homeostasis / genetics
  • Homeostasis / physiology
  • Immunohistochemistry
  • Male
  • Microglia / cytology
  • Microglia / metabolism
  • Microscopy, Electron, Transmission
  • Mitochondria / metabolism
  • Multiple Sclerosis / genetics
  • Multiple Sclerosis / metabolism
  • Oligodendroglia / cytology*
  • Oligodendroglia / metabolism*
  • Phagocytosis / genetics
  • Phagocytosis / physiology
  • Protein Processing, Post-Translational
  • Rats
  • Real-Time Polymerase Chain Reaction
  • Remyelination / genetics
  • Remyelination / physiology


  • Glutathione Transferase
  • glutathione S-transferase Mu 2
  • Caspase 8