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

Karl E. Carlström (), Keying Zhu, Ewoud Ewing, Inge E. Krabbendam, Robert A. Harris, Ana Mendanha Falcão, Maja Jagodic, Gonçalo Castelo-Branco and Fredrik Piehl
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Karl E. Carlström: Karolinska Institutet, Center for Molecular Medicine, Karolinska Hospital at Solna
Keying Zhu: Karolinska Institutet, Center for Molecular Medicine, Karolinska Hospital at Solna
Ewoud Ewing: Karolinska Institutet, Center for Molecular Medicine, Karolinska Hospital at Solna
Inge E. Krabbendam: Karolinska Institutet, Center for Molecular Medicine, Karolinska Hospital at Solna
Robert A. Harris: Karolinska Institutet, Center for Molecular Medicine, Karolinska Hospital at Solna
Ana Mendanha Falcão: Karolinska Institutet
Maja Jagodic: Karolinska Institutet, Center for Molecular Medicine, Karolinska Hospital at Solna
Gonçalo Castelo-Branco: Karolinska Institutet
Fredrik Piehl: Karolinska Institutet, Center for Molecular Medicine, Karolinska Hospital at Solna

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-17871-5

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