Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients.

Détails

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Etat: Public
Version: Author's accepted manuscript
ID Serval
serval:BIB_E4804562B409
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients.
Périodique
Molecular psychiatry
Auteur(s)
Monin A., Baumann P.S., Griffa A., Xin L., Mekle R., Fournier M., Butticaz C., Klaey M., Cabungcal J.H., Steullet P., Ferrari C., Cuenod M., Gruetter R., Thiran J.P., Hagmann P., Conus P., Do K.Q.
ISSN
1476-5578 (Electronic)
ISSN-L
1359-4184
Statut éditorial
Publié
Date de publication
07/2015
Peer-reviewed
Oui
Volume
20
Numéro
7
Pages
827-838
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
Schizophrenia pathophysiology implies both abnormal redox control and dysconnectivity of the prefrontal cortex, partly related to oligodendrocyte and myelin impairments. As oligodendrocytes are highly vulnerable to altered redox state, we investigated the interplay between glutathione and myelin. In control subjects, multimodal brain imaging revealed a positive association between medial prefrontal glutathione levels and both white matter integrity and resting-state functional connectivity along the cingulum bundle. In early psychosis patients, only white matter integrity was correlated with glutathione levels. On the other side, in the prefrontal cortex of peripubertal mice with genetically impaired glutathione synthesis, mature oligodendrocyte numbers, as well as myelin markers, were decreased. At the molecular levels, under glutathione-deficit conditions induced by short hairpin RNA targeting the key glutathione synthesis enzyme, oligodendrocyte progenitors showed a decreased proliferation mediated by an upregulation of Fyn kinase activity, reversed by either the antioxidant N-acetylcysteine or Fyn kinase inhibitors. In addition, oligodendrocyte maturation was impaired. Interestingly, the regulation of Fyn mRNA and protein expression was also impaired in fibroblasts of patients deficient in glutathione synthesis. Thus, glutathione and redox regulation have a critical role in myelination processes and white matter maturation in the prefrontal cortex of rodent and human, a mechanism potentially disrupted in schizophrenia.

Mots-clé
Adult, Animals, Brain/pathology, Brain/physiopathology, Cells, Cultured, Female, Fibroblasts/metabolism, Glutamate-Cysteine Ligase/genetics, Glutamate-Cysteine Ligase/metabolism, Glutathione/deficiency, Humans, Male, Mice, Knockout, Myelin Sheath/pathology, Myelin Sheath/physiology, Oligodendroglia/pathology, Oligodendroglia/physiology, Proto-Oncogene Proteins c-fyn/metabolism, Rats, Wistar, Schizophrenia/drug therapy, Schizophrenia/pathology, Schizophrenia/physiopathology, White Matter/pathology, White Matter/physiopathology, Young Adult
Pubmed
Web of science
Création de la notice
07/11/2014 11:40
Dernière modification de la notice
20/08/2019 17:08
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