Abstract
We previously reported that SNPs near TSPAN5 were associated with plasma serotonin (5-HT) concentrations which were themselves associated with selective serotonin reuptake inhibitor treatment outcomes in patients with major depressive disorder (MDD). TSPAN5 SNPs were also associated with alcohol consumption and alcohol use disorder (AUD) risk. The present study was designed to explore the biological function of TSPAN5 with a focus on 5-HT and kynurenine concentrations in the tryptophan pathway. Ethanol treatment resulted in decreased 5-HT concentrations in human induced pluripotent stem cell (iPSC)-derived neuron culture media, and the downregulation of gene expression of TSPAN5, DDC, MAOA, MAOB, TPH1, and TPH2 in those cells. Strikingly, similar observations were made when the cells were treated with acamprosate—an FDA approved drug for AUD therapy. These results were replicated in iPSC-derived astrocytes. Furthermore, TSPAN5 interacted physically with proteins related to clathrin and other vesicle-related proteins, raising the possibility that TSPAN5 might play a role in vesicular function in addition to regulating expression of genes associated with 5-HT biosynthesis and metabolism. Downregulation of TSPAN5 expression by ethanol or acamprosate treatment was also associated with decreased concentrations of kynurenine, a major metabolite of tryptophan that plays a role in neuroinflammation. Knockdown of TSPAN5 also influenced the expression of genes associated with interferon signaling pathways. Finally, we determined that TSPAN5 SNPs were associated with acamprosate treatment outcomes in AUD patients. In conclusion, TSPAN5 can modulate the concentrations of 5-HT and kynurenine. Our data also highlight a potentially novel pharmacogenomic mechanism related to response to acamprosate.
Highlights
Supplementary information The online version of this article contains supplementary material, which is available to authorized users.We previously reported that TSPAN5 eQTL SNPs on chromosome 4 were associated with variation in plasma serotonin (5-HT) concentrations which were themselves correlated with selective serotonin reuptake inhibitor treatment outcomes in patients with major depressive disorder (MDD) [1]
As a result of this growing body of evidence that TSPAN5 may play a role in both MDD and alcohol use disorder (AUD) risk, the present study was designed to explore the biological function of TSPAN5 with a focus on the tryptophan pathway using human induced pluripotent stem cell (iPSC)-derived CNS cells exposed to either ethanol (EtOH) or acamprosate—an FDA approved medication for the treatment of AUD [7]
TSPAN5 expression was significantly down-regulated in iPSC-derived forebrain neurons after EtOH (25 mM) exposure that is considered physiologically relevant, with 25 mM EtOH being slightly higher than the 0.08% blood alcohol concentration (BAC) required to be legally intoxicated in most states in the United State [28] (Fig. 1b)
Summary
We previously reported that TSPAN5 eQTL SNPs on chromosome 4 were associated with variation in plasma serotonin (5-HT) concentrations which were themselves correlated with selective serotonin reuptake inhibitor treatment outcomes in patients with major depressive disorder (MDD) [1]. It should be pointed out that depression is the most common psychiatric co-morbidity among AUD patients [2,3,4]. A recent genome-wide association study (GWAS) of alcohol consumption in UK Biobank participants identified a series of genome-wide significant variants on chromosome 4 [5]. Several of those SNPs (rs3114045, rs193099203 and rs9991733) are trans-eQTLs in the brain for TSPAN5 which maps to chromosome 4.
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