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

Autor:	Carlström KE; Department of Clinical Neurosciences, Karolinska Institutet, Center for Molecular Medicine, Karolinska Hospital at Solna, 17177, Stockholm, Sweden. karl.carlstrom@ki.se., Zhu K; Department of Clinical Neurosciences, Karolinska Institutet, Center for Molecular Medicine, Karolinska Hospital at Solna, 17177, Stockholm, Sweden., Ewing E; Department of Clinical Neurosciences, Karolinska Institutet, Center for Molecular Medicine, Karolinska Hospital at Solna, 17177, Stockholm, Sweden., Krabbendam IE; Department of Clinical Neurosciences, Karolinska Institutet, Center for Molecular Medicine, Karolinska Hospital at Solna, 17177, Stockholm, Sweden., Harris RA; Department of Clinical Neurosciences, Karolinska Institutet, Center for Molecular Medicine, Karolinska Hospital at Solna, 17177, Stockholm, Sweden., Falcão AM; Laboratory of Molecular Neurobiology, Department Medical Biochemistry and Biophysics, Biomedicum, Karolinska Institutet, 17177, Stockholm, Sweden.; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Minho, Portugal., Jagodic M; Department of Clinical Neurosciences, Karolinska Institutet, Center for Molecular Medicine, Karolinska Hospital at Solna, 17177, Stockholm, Sweden., Castelo-Branco G; Laboratory of Molecular Neurobiology, Department Medical Biochemistry and Biophysics, Biomedicum, Karolinska Institutet, 17177, Stockholm, Sweden.; Ming Wai Lau Centre for Reparative Medicine, Stockholm node, Karolinska Institutet, Stockholm, Sweden., Piehl F; Department of Clinical Neurosciences, Karolinska Institutet, Center for Molecular Medicine, Karolinska Hospital at Solna, 17177, Stockholm, Sweden.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2020 Aug 13; Vol. 11 (1), pp. 4071. Date of Electronic Publication: 2020 Aug 13.
DOI:	10.1038/s41467-020-17871-5
Abstrakt:	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.
Databáze:	MEDLINE
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