Aberrant Tyrosine Transport Across the Cell Membrane in Patients With Schizophrenia

Flyckt, Lena; Venizelos, Nikolaos; Edman, Gunnar; Bjerkenstedt, Lars; Hagenfeldt, Lars; Wiesel, Frits‐Axel

doi:10.1001/archpsyc.58.10.953

Cited by 36 publications

(33 citation statements)

References 34 publications

(47 reference statements)

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“…Moreover, interventions such as treatment with anti-inflammatory agents are speculated to prevent the development of chronic neuropsychiatric complications [15]. Neuropsychiatric symptoms arise due to disturbed neurotransmission, which could partly be caused by disturbed transportation of the dopamine precursor tyrosine, as has been demonstrated in many studies [19, 23, 33]. This evidence suggests a possible role of cytokines and disturbed tyrosine transportation in the pathogenesis of neuropsychiatric disorders, but the underlying mechanisms are not completely elucidated.…”

Section: Discussionmentioning

confidence: 99%

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Proinflammatory Cytokines and Oxidative Stress Decrease the Transport of Dopamine Precursor Tyrosine in Human Fibroblasts

2017

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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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Section: Discussionmentioning

confidence: 99%

“…Decreased transport of tyrosine has been demonstrated by our group in fibroblasts obtained from patients with schizophrenia [19-21], autism [22], and bipolar disorder [23]. Furthermore, decreased transport of tryptophan has been observed in fibroblasts of children with ADHD in comparison to controls [24].…”

Section: Introductionmentioning

confidence: 98%

Proinflammatory Cytokines and Oxidative Stress Decrease the Transport of Dopamine Precursor Tyrosine in Human Fibroblasts

2017

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“…Tyrosine uptake assays were carried out with cell lines of 10 patients and 10 healthy controls. All cell lines were obtained from a Biobank, and the same fibroblasts were included in previous studies [4,5]. Patients fulfilled the diagnostic criteria of schizophrenia according to DSM-III-R [5].…”

Section: Methodsmentioning

confidence: 99%

“…Aberrant transport of tyrosine across the fibroblast membranes of patients with schizophrenia, indicated by a lower maximal transport capacity ( V max ) and a lower affinity constant ( K m ), has been demonstrated by some [5,6] but not all studies [7,8]. Dietary depletion of tyrosine resulted in reduced dopamine concentration in the striatum [9] and impaired cognitive functioning in healthy controls [10].…”

Section: Introductionmentioning

confidence: 99%

Genetic and Functional Study of <smlcap>L</smlcap>-Type Amino Acid Transporter 1 in Schizophrenia

et al. 2016

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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.

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“…Consisting findings of aberrant amino acid transport across the cell membrane of fibroblast cells from patients with SZ, BD, autism and Attention Deficit Hyperactivity Disorder (ADHD) indicate alterations in the expression levels of the genes encoding the amino acid transporters [15,20,53,54].…”

Section: Amino Acid Transport and Bdmentioning

confidence: 99%

Gene Expression Analysis of Fibroblasts from Patients with Bipolar Disorder

Logotheti¹,

Papadodima²

2016

J Neuropsychopharmacol Mental Health

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Bipolar disorder is a severe, lifelong psychiatric disease. The main underlying pathophysiology of the disease is still incomprehensible. Various studies have suggested that many genes of small impact in combination with environmental factors contribute to the expression of the disease. In this study comparative transcriptomic profiling to characterize skin fibroblasts' gene expression of bipolar disorder patients compared to healthy controls has been performed. Skin fibroblast cells from bipolar disorder patients (n=10) and marched healthy controls (n=5) have been cultured. RNA was extracted and then hybridized onto Illumina Human HT-12 v4 Expression BeadChips. Differentially expressed genes between bipolar disorder samples and healthy controls were identified by performing unequal t-test on log 2 transformed expression values. The resulting gene list was obtained by setting the p-value threshold to 0.05 and by removing genes that presented a fold change ≥ |0.5| (in log 2 scale). We concluded to 457 differentially expressed genes. Among them 127 showed an upregulation and 330 were downregulated. Τhe expression alterations of selected genes were validated by quantitative real-time polymerase chain reaction. In order to derive better insight into the biological mechanisms related to the differentially expressed genes, the lists of significant genes were subjected to pathway analysis and target prioritization indicating various processes such as calcium ion homeostasis, positive regulation of apoptotic process and cellular response to retinoic acid.

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Aberrant Tyrosine Transport Across the Cell Membrane in Patients With Schizophrenia

Cited by 36 publications

References 34 publications

Proinflammatory Cytokines and Oxidative Stress Decrease the Transport of Dopamine Precursor Tyrosine in Human Fibroblasts

Proinflammatory Cytokines and Oxidative Stress Decrease the Transport of Dopamine Precursor Tyrosine in Human Fibroblasts

Genetic and Functional Study of <smlcap>L</smlcap>-Type Amino Acid Transporter 1 in Schizophrenia

Gene Expression Analysis of Fibroblasts from Patients with Bipolar Disorder

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