Abstract

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.

Highlights

  • The system xc- is a sodium-independent antiporter, which imports cystine and exports glutamate in a 1:1 ratio.[1]

  • GCLC high-risk genotypes are associated with increased levels of xCT mRNA

  • Levels of SLC7A11 and SLC3A2 were similar between patients and controls both in vehicle (FC = −1.03; p-value = 0.85; FC = 1.04; p-value = 0.73) and tBHQ-treated condition (FC = 1.06; p-value = 0.72, FC = 1.04; p-value = 0.70)

Read more

Summary

Introduction

The system xc- is a sodium-independent antiporter, which imports cystine and exports glutamate in a 1:1 ratio.[1] Intracellular cystine is readily reduced to cysteine, the limiting precursor for glutathione (GSH) synthesis. XCT is the specific chain and an increase of gene expression often reflects an enhancement of cystine transport.[3,4,5] xCT is stabilized at the membrane by CD44, a receptor for hyaluronic acid, whose expression increases intracellular levels of cysteine and GSH.[6]. The Nrf[2] inducer tert-butyl-hydroquinone (tBHQ), as well as the inhibitor of GSH synthesis buthionine sulfoximine (BSO), robustly increase xCT protein levels in cell culture.[14,15]

Methods
Results
Conclusion

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call

Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.