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  • 1.
    Comasco, Erika
    et al.
    Uppsala University.
    Vumma, Ravi
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Toffoletto, Simone
    Uppsala University.
    Johansson, Jessica
    Örebro University.
    Flyckt, Lena
    Karolinska institutet.
    Lewander, Tommy
    Örebro university.
    Oreland, Lars
    Uppsala university.
    Bjerkenstedt, Lars
    Strömstad Academy, Strömstad, Sweden.
    Andreou, Dimitrios
    Karolinska institutet.
    Söderman, Erik
    Karolinska institutet.
    Terenius, Lars
    Karolinska institutet.
    Agartz, Ingrid
    Karolinska institutet ; University of Oslo, Norway ; Diakonhjemmet Hospital, Oslo, Norway.
    Jönsson, Erik G
    Karolinska institutet ; University of Oslo, Norway.
    Venizelos, Nikolaos
    Örebro university.
    Genetic and Functional Study of L-Type Amino Acid Transporter 1 in Schizophrenia.2016In: Neuropsychobiology, ISSN 0302-282X, E-ISSN 1423-0224, Vol. 74, no 2, p. 96-103Article in journal (Refereed)
    Abstract [en]

    Schizophrenia involves neural catecholaminergic dysregulation. Tyrosine is the precursor of catecholamines, and its major transporter, according to studies on fibroblasts, in the brain is the L-type amino acid transporter 1 (LAT1). The present study assessed haplotype tag single-nucleotide polymorphisms (SNPs) of the SLC7A5/LAT1 gene in 315 patients with psychosis within the schizophrenia spectrum and 233 healthy controls to investigate genetic vulnerability to the disorder as well as genetic relationships to homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG), the major catecholamine metabolites in the cerebrospinal fluid (CSF). Moreover, the involvement of the different isoforms of the system L in tyrosine uptake and LAT1 tyrosine kinetics were studied in fibroblast cell lines of 10 patients with schizophrenia and 10 healthy controls. The results provide suggestive evidence of individual vulnerability to schizophrenia related to the LAT1 SNP rs9936204 genotype. A number of SNPs were nominally associated with CSF HVA and MHPG concentrations but did not survive correction for multiple testing. The LAT1 isoform was confirmed as the major tyrosine transporter in patients with schizophrenia. However, the kinetic parameters (maximal transport capacity, affinity of the binding sites, and diffusion constant of tyrosine transport through the LAT1 isoform) did not differ between patients with schizophrenia and controls. The present genetic findings call for independent replication in larger samples, while the functional study seems to exclude a role of LAT1 in the aberrant transport of tyrosine in fibroblasts of patients with schizophrenia.

  • 2.
    Vumma, Ravi
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Johansson, Jessica
    Örebro University.
    Venizelos, Nikolaos
    Örebro University.
    Proinflammatory cytokines and oxidative stress decrease the transport of dopamine precursor tyrosine in human fibroblasts2017In: Neuropsychobiology, ISSN 0302-282X, E-ISSN 1423-0224, Vol. 75, no 4, p. 178-184Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Proinflammatory cytokines and oxidative stress responses have been extensively implicated in the pathophysiology of neuropsychiatric disorders over the past 2 decades. Moreover, disturbed transport of the dopamine precursor (i.e., the amino acid tyrosine) has been demonstrated, in different studies, across fibroblast cell membranes obtained from neuropsychiatric patients. However, the role and influences of proinflammatory cytokines and oxidative stress, and the reasons for disturbed tyrosine transport in neuropsychiatric disorders, are still not evaluated.

    AIMS: The present study aimed to assess the role of proinflammatory cytokines and oxidative stress, indicated in many neuropsychiatric disorders, in tyrosine transportation, by using human skin-derived fibroblasts.

    METHODS: Fibroblasts obtained from a healthy control were used in this study. Fibroblasts were treated with proinflammatory cytokines (IL-1β, IFN-γ, IL-6, TNF-α), their combinations, and oxidative stress, optimized for concentrations and incubation time, to analyze the uptake of 14C-tyrosine compared to untreated controls.

    RESULTS AND CONCLUSION: This study demonstrates that proinflammatory cytokines and oxidative stress decrease the transport of tyrosine (47% and 33%, respectively), which can alter dopamine synthesis. The functionality of the tyrosine transporter could be a new potential biomarker to target for discovering new drugs to counteract the effects of proinflammatory cytokines and oxidative stress in the pathophysiology of neuropsychiatric disorders.

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