Soluble Urokinase-Type Plasminogen Activator Receptor Levels in Patients With Schizophrenia

Nielsen, Jimmi; Røge, Rasmus; Pristed, Sofie Gry; Viuff, Anne Grethe; Ullum, Henrik; Thørner, Lise Wegner; Werge, Thomas; Vang, Torkel

doi:10.1093/schbul/sbu118

Cited by 18 publications

(11 citation statements)

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“…In support of this idea, there is evidence that increased levels of inflammatory cytokines, following a genetic insult or exposure to oxidative stress or infectious agents, can contribute to cognitive, negative, and positive symptoms in schizophrenia [ 40 ]. Elevated levels of cytokines have been reported in postmortem brain and peripheral blood of subjects with schizophrenia [ 115 , 116 , 117 ]. Neuroimaging studies have shown active inflammation in the brains of patients with psychosis [ 118 ].…”

Section: Discussionmentioning

confidence: 99%

Reduced Slc1a1 expression is associated with neuroinflammation and impaired sensorimotor gating and cognitive performance in mice: Implications for schizophrenia

2017

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We previously reported a 84-Kb hemi-deletion copy number variant at the SLC1A1 gene locus that reduces its expression and appeared causally linked to schizophrenia. In this report, we characterize the in vivo and in vitro consequences of reduced expression of Slc1a1 in mice. Heterozygous (HET) Slc1a1+/- mice, which more closely model the hemi-deletion we found in human subjects, were examined in a series of behavioral, anatomical and biochemical assays. Knockout (KO) mice were also included in the behavioral studies for comparative purposes. Both HET and KO mice exhibited evidence of increased anxiety-like behavior, impaired working memory, decreased exploratory activity and impaired sensorimotor gating, but no changes in overall locomotor activity. The magnitude of changes was approximately equivalent in the HET and KO mice suggesting a dominant effect of the haploinsufficiency. Behavioral changes in the HET mice were accompanied by reduced thickness of the dorsomedial prefrontal cortex. Whole transcriptome RNA-Seq analysis detected expression changes of genes and pathways involved in cytokine signaling and synaptic functions in both brain and blood. Moreover, the brains of Slc1a1+/- mice displayed elevated levels of oxidized glutathione, a trend for increased oxidative DNA damage, and significantly increased levels of cytokines. This latter finding was further supported by SLC1A1 knockdown and overexpression studies in differentiated human neuroblastoma cells, which led to decreased or increased cytokine expression, respectively. Taken together, our results suggest that partial loss of the Slc1a1 gene in mice causes haploinsufficiency associated with behavioral, histological and biochemical changes that reflect an altered redox state and may promote the expression of behavioral features and inflammatory states consistent with those observed in schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Reduced Slc1a1 expression is associated with neuroinflammation and impaired sensorimotor gating and cognitive performance in mice: Implications for schizophrenia

2017

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“…suPAR levels are independent of the circadian rhythm, not sensitive to repeated freeze-thaw [ 25 , 26 ], and not strongly linked to BMI [ 27 ]. However, sex, age and current smoking has been reported to be associated with suPAR levels [ 36 ]. We found correlations between suPAR levels, age and BMI, but as a limitation of this study we were unable to adjust for current smoking.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, suPAR levels in blood from patients with schizophrenia were compared to healthy controls [ 36 ]. Interestingly, the mean values of suPAR levels were higher in patients with schizophrenia and the mean value of suPAR corresponded to the suPAR levels in suicide attempters of this study (i.e.…”

Section: Discussionmentioning

confidence: 99%

Increased Soluble Urokinase-Type Plasminogen Activator Receptor (suPAR) Levels in Plasma of Suicide Attempters

et al. 2015

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The soluble form of the urokinase receptor, suPAR, has been suggested as a novel biomarker of low-grade inflammation. Activation of the immune system has been proposed to contribute to the development of depression and suicidal behavior. In order to identify depressed and suicidal individuals who could benefit from an anti-inflammatory treatment, a reliable biomarker of low-grade inflammation is vital. This study evaluates plasma suPAR levels as a biomarker of low-grade inflammation in patients with major depressive disorder and in patients who recently attempted suicide. The plasma suPAR and an established biomarker, C reactive protein (CRP) of suicide attempters (n = 54), depressed patients (n = 19) and healthy controls (n = 19) was analyzed with enzyme-linked immunosorbent assays. The biomarker attributes of sensitivity and sensibility were evaluated using ROC curve analysis. Both the depressed patients and suicide attempters had increased plasma suPAR. The levels of suPAR discriminated better between controls and suicide attempters than did CRP. In the future, plasma suPAR might be a superior prognosticator regarding outcome of treatment applying conventional antidepressants in conjunction with anti-inflammatory drugs.

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“…This emerging school of thought postulates that increased risk of psychosis occurs as a result of elevated proinflammatory molecule production following exposure to oxidative stress, infectious agents, toxins, or even acute psychological stressors [6]. In support of this idea, several cytokines have been reported to be elevated in plasma from schizophrenic subjects [7, 8], and neuroimaging studies have shown active inflammation in the brains of patients with psychosis [9]. Conversely, subjects with psychosis exhibit reduced symptoms when administered anti-inflammatory agents [11, 12].…”

Section: Introductionmentioning

confidence: 99%

Characterization of a Novel Mutation in <b><i>SLC1A1 </i></b>Associated with Schizophrenia

Afshari¹,

Myles-Worsley

Cohen

et al. 2015

Complex Psychiatry

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We have recently described a hemi-deletion on chromosome 9p24.2 at the SLC1A1 gene locus and its co-segregation with schizophrenia in an extended Palauan pedigree. This finding represents a point of convergence for several pathophysiological models of schizophrenia. The present report sought to characterize the biological consequences of this hemi-deletion. Dual luciferase assays demonstrated that the partially deleted allele (lacking exon 1 and the native promoter) can drive expression of a 5′-truncated SLC1A1 using sequence upstream of exon 2 as a surrogate promoter. However, confocal microscopy and electrophysiological recordings demonstrate that the 5′-truncated SLC1A1 lacks normal membrane localization and glutamate transport ability. To identify downstream consequences of the hemi-deletion, we first used a themed qRT-PCR array to compare expression of 84 GABA and glutamate genes in RNA from peripheral blood leukocytes in deletion carriers (n = 11) versus noncarriers (n = 8) as well as deletion carriers with psychosis (n = 5) versus those without (n = 3). Then, targeted RNA-Seq (TREx) was used to quantify expression of 375 genes associated with neuropsychiatric disorders in HEK293 cells subjected to either knockdown of SLC1A1 or overexpression of full-length or 5′-truncated SLC1A1. Expression changes of several genes strongly implicated in schizophrenia pathophysiology were detected (e.g. SLC1A2, SLC1A3, SLC1A6, SLC7A11, GRIN2A, GRIA1 and DLX1).

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Soluble Urokinase-Type Plasminogen Activator Receptor Levels in Patients With Schizophrenia

Abstract: Patients with schizophrenia had significantly higher suPAR levels than healthy controls. Further studies are warranted to clarify if elevated suPAR levels are involved in the pathophysiology of schizophrenia and/or the increased mortality found in patients with schizophrenia.

Cited by 18 publications

References 50 publications

Reduced Slc1a1 expression is associated with neuroinflammation and impaired sensorimotor gating and cognitive performance in mice: Implications for schizophrenia

Reduced Slc1a1 expression is associated with neuroinflammation and impaired sensorimotor gating and cognitive performance in mice: Implications for schizophrenia

Increased Soluble Urokinase-Type Plasminogen Activator Receptor (suPAR) Levels in Plasma of Suicide Attempters

Characterization of a Novel Mutation in <b><i>SLC1A1 </i></b>Associated with Schizophrenia

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