Implication of the glutamate-cystine antiporter xCT in schizophrenia cases linked to impaired GSH synthesis.

Détails

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Etat: Public
Version: Final published version
ID Serval
serval:BIB_7B369843D5D9
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Implication of the glutamate-cystine antiporter xCT in schizophrenia cases linked to impaired GSH synthesis.
Périodique
NPJ schizophrenia
Auteur(s)
Fournier M., Monin A., Ferrari C., Baumann P.S., Conus P., Do K.
ISSN
2334-265X (Print)
ISSN-L
2334-265X
Statut éditorial
Publié
Date de publication
18/09/2017
Peer-reviewed
Oui
Volume
3
Numéro
1
Pages
31
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: epublish
Résumé
xCT is the specific chain of the cystine/glutamate antiporter, which is widely reported to support anti-oxidant defenses in vivo. xCT is therefore at the crossroads between two processes that are involved in schizophrenia: oxidative stress and glutamatergic neurotransmission. But data from human studies implicating xCT in the illness and clarifying the upstream mechanisms of xCT imbalance are still scarce. Low glutathione (GSH) levels and genetic risk in GCLC (Glutamate-Cysteine Ligase Catalytic subunit), the gene of limiting synthesizing enzyme for GSH, are both associated with schizophrenia. In the present study, we aimed at determining if xCT regulation by the redox system is involved in schizophrenia pathophysiology. We assessed whether modulating GCLC expression impact on xCT expression and activity (i) in fibroblasts from patients and controls with different GCLC genotypes which are known to affect GCLC regulation and GSH levels; (ii) in rat brain glial cells, i.e., astrocytes and oligodendrocytes, with a knock-down of GCLC. Our results highlight that decreased GCLC expression leads to an upregulation of xCT levels in patients' fibroblasts as well as in astrocytes. These results support the implication of xCT dysregulation in illness pathophysiology and further indicate that it can result from redox changes. Additionally, we showed that these anomalies may already take place at early stages of psychosis and be more prominent in a subgroup of patients with GCLC high-risk genotypes. These data add to the existing evidence identifying the inflammatory/redox systems as important targets to treat schizophrenia already at early stages.
ANTIOXIDANT DEFICIT INCREASES A KEY NEUROTRANSMITTER TRANSPORTER: Deficit of antioxidant synthesis in schizophrenia leads to oxidative stress and changes in neurotransmitter transporter. Led by Kim Do, a team of researchers from Lausanne University in Switzerland investigated the role of the cell-surface transport protein xCT in schizophrenia. They found that an enzyme responsible for antioxidant production is disturbed in patients. This leads to decreased antioxidant levels and consequently to oxidative stress-i.e. the accumulation of reactive oxygen molecules, damaging the cells component and impairing cell functioning-which in turn affects the functioning of the antioxidant pathway, including xCT. xCT, which exports the neurotransmitter glutamate, is thus overproduced in schizophrenia. The resulting increase of neurotransmitter activity, alongside the increase in oxidative stress, is thought to play a major role in the pathophysiology of schizophrenia, including at early stages of the disease.

Pubmed
Open Access
Oui
Création de la notice
26/09/2017 14:58
Dernière modification de la notice
20/08/2019 15:37
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