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Functional characterization of the schizophrenia associated gene AS3MT identifies a role in neuronal development.

ABSTRACT: Genome-wide association studies (GWAS) have identified multiple genomic regions associated with schizophrenia, although many variants reside in noncoding regions characterized by high linkage disequilibrium (LD) making the elucidation of molecular mechanisms challenging. A genomic region on chromosome 10q24 has been consistently associated with schizophrenia with risk attributed to the AS3MT gene. Although AS3MT is hypothesized to play a role in neuronal development and differentiation, work to fully understand the function of this gene has been limited. In this study we explored the function of AS3MT using a neuronal cell line (SH-SY5Y). We confirm previous findings of isoform specific expression of AS3MT during SH-SY5Y differentiation toward neuronal fates. Using CRISPR-Cas9 gene editing we generated AS3MT knockout SH-SY5Y cell lines and used RNA-seq to identify significant changes in gene expression in pathways associated with neuronal development, inflammation, extracellular matrix formation, and RNA processing, including dysregulation of other genes strongly implicated in schizophrenia. We did not observe any morphological changes in cell size and neurite length following neuronal differentiation and MAP2 immunocytochemistry. These results provide novel insights into the potential role of AS3MT in brain development and identify pathways through which genetic variation in this region may confer risk for schizophrenia.

SUBMITTER: Washer SJ

PROVIDER: S-EPMC9546433 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Functional characterization of the schizophrenia associated gene AS3MT identifies a role in neuronal development.

Washer Sam J SJ Flynn Robert R Oguro-Ando Asami A Hannon Eilis E Burrage Joe J Jeffries Aaron A Mill Jonathan J Dempster Emma L EL

American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 20220619 5

Genome-wide association studies (GWAS) have identified multiple genomic regions associated with schizophrenia, although many variants reside in noncoding regions characterized by high linkage disequilibrium (LD) making the elucidation of molecular mechanisms challenging. A genomic region on chromosome 10q24 has been consistently associated with schizophrenia with risk attributed to the AS3MT gene. Although AS3MT is hypothesized to play a role in neuronal development and differentiation, work to ...[more]

PMID: 35719055

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Project description:Schizophrenia is a devastating neuropsychiatric disease with a globally 1% life-long prevalence. Clinical studies have linked Zswim6 mutations to developmental and neurological diseases, including schizophrenia. Zswim6's function remains largely unknown. Given the involvement of Zswim6 in schizophrenia and schizophrenia as a neurodevelopmental disease, it is important to understand the spatiotemporal expression pattern of Zswim6 in the developing brain. Here, we performed a comprehensive analysis of the spatiotemporal expression pattern of Zswim6 in the mouse forebrain by in situ hybridization with radioactive and non-radioactive-labeled riboprobes. Zswim6 mRNA was detected as early as E11.5 in the ventral forebrain. At E11.5-E13.5, Zswim6 was highly expressed in the lateral ganglionic eminence (LGE). The LGE consisted of two progenitor populations. Dlx+;Er81+ cells in dorsal LGE comprised progenitors of olfactory bulb interneurons, whereas Dlx+;Isl1+ progenitors in ventral LGE gave rise to striatal projection neurons. Zswim6 was not colocalized with Er81 in the dorsal LGE. In the ventral LGE, Zswim6 was colocalized with striatal progenitor marker Nolz-1. Zswim6 was highly expressed in the subventricular zone (SVZ) of LGE in which progenitors undergo the transition from proliferation to differentiation. Double labeling showed that Zswim6 was not colocalized with proliferation marker Ki67 but was colocalized with differentiation marker Tuj1 in the SVZ, suggesting Zswim6 expression in early differentiating neurons. Zswim6 was also expressed in the adjacent structures of medial and caudal ganglionic eminences (MGE, CGE) that contained progenitors of cortical interneurons. At E15.5 and E17.5, Zswim6 was expressed in several key brain regions that were involved in the pathogenesis of schizophrenia, including the striatum, cerebral cortex, hippocampus, and medial habenular nucleus. Zswim6 was persistently expressed in the postnatal brain. Cell type analysis indicated that Zswim6 mRNA was colocalized with D1R-expressing striatonigral and D2R-expressing striatopallidal neurons of the adult striatum with a higher colocalization in striatopallidal neurons. These findings are of particular interest as striatal dopamine D2 receptors are known to be involved in the pathophysiology of schizophrenia. In summary, the comprehensive analysis provides an anatomical framework for the study of Zswim6 function and Zswim6-associated neurological disorders.

Project description:ImportanceIn schizophrenia, working memory deficits appear to reflect abnormalities in the generation of gamma oscillations in the dorsolateral prefrontal cortex. The generation of gamma oscillations requires the phasic excitation of inhibitory parvalbumin-containing interneurons. Thus, gamma oscillations depend, in part, on the number of synaptic glutamate receptors on parvalbumin interneurons. However, little is known about the molecular factors that regulate glutamate receptor-mediated excitation of parvalbumin interneurons in schizophrenia.ObjectiveTo quantify in individuals with schizophrenia the expression of immediate early genes (NARP, ARC, and SGK1) regulating glutamate synaptic neurotransmission.Design, setting, and participantsPostmortem brain specimens (n = 206) were obtained from individuals with schizophrenia, bipolar disorder, or major depressive disorder and from well-matched healthy persons (controls). For a study of brain tissue, quantitative polymerase chain reaction, in situ hybridization, or microarray analyses were used to measure transcript levels in the dorsolateral prefrontal cortex at gray matter, laminar, and cellular levels of resolutions. This study was conducted between January 1, 2013, and November 30, 2014.Main outcomes and measuresExpression levels for NARP, ARC, and SGK1 messenger RNA (mRNA) were compared between specimens from individuals with schizophrenia and controls. Diagnostic specificity was assessed by quantifying NARP mRNA levels in specimens from individuals with mood disorders.ResultsBy quantitative polymerase chain reaction, levels of NARP mRNA were significantly lower by 25.6% in specimens from individuals with schizophrenia compared with the controls (mean [SD], 0.036 [0.018] vs 0.049 [0.015]; F1,114 = 21.0; P < .001). Levels of ARC (F1,112 = 0.93; P = .34) and SGK1 (F1,110 = 2.52; P = .12) were not significant. These findings were supported by in situ hybridization (NARP; individuals with schizophrenia vs controls: 40.1% lower [P = .003]) and microarray analyses (NARP; individuals with schizophrenia vs controls: 12.2% lower in layer 3 [P = .11] and 14.6% lower in layer 5 pyramidal cells [P = .001]). In schizophrenia specimens, NARP mRNA levels were positively correlated with GAD67 mRNA (r = 0.55; P < .001); the expression of GAD67 mRNA in parvalbumin interneurons is activity dependent. The NARP mRNA levels were also lower than healthy controls in bipolar disorder (-18.2%; F1,60 = 11.39; P = .001) and major depressive disorder (-21.7%; F1,30 = 5.36; P = .03) specimens, especially those from individuals with psychosis. In all 3 diagnostic groups, NARP mRNA levels were positively correlated (all r ≥ 0.53; all P ≤ .02) with somatostatin mRNA, the expression of which is activity dependent.Conclusions and relevanceGiven the role of NARP in the formation of excitatory inputs to parvalbumin (and perhaps somatostatin) interneurons, our findings suggest that lower NARP mRNA expression contributes to lower excitatory drive onto parvalbumin interneurons in schizophrenia. This reduced excitatory drive may lead to lower synthesis of γ-aminobutyric acid in these interneurons, contributing to a reduced capacity to generate the gamma oscillations required for working memory.

Project description:BackgroundArsenic (As) occurs as monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) in humans, and the methylation pattern demonstrates large interindividual differences. The fraction of urinary MMA is a marker for susceptibility to As-related diseases.ObjectivesWe evaluated the impact of polymorphisms in five methyltransferase genes on As metabolism in two populations, one in South America and one in Southeast Asia. The methyltransferase genes were arsenic(+III oxidation state) methyltransferase (AS3MT), DNA-methyltransferase 1a and 3b (DNMT1a and DNMT3b, respectively), phosphatidylethanolamine N-methyltransferase (PEMT), and betaine-homocysteine methyltransferase (BHMT). AS3MT expression was analyzed in peripheral blood.MethodsSubjects were women exposed to As in drinking water in the Argentinean Andes [n = 172; median total urinary As (U-As), 200 µg/L] and in rural Bangladesh (n = 361; U-As, 100 µg/L; all in early pregnancy). Urinary As metabolites were measured by high-pressure liquid chromatography/inductively coupled plasma mass spectrometry. Polymorphisms (n = 22) were genotyped with Sequenom, and AS3MT expression was measured by quantitative real-time polymerase chain reaction using TaqMan expression assays.ResultsSix AS3MT polymorphisms were significantly associated with As metabolite patterns in both populations (p ≤ 0.01). The most frequent AS3MT haplotype in Bangladesh was associated with a higher percentage of MMA (%MMA), and the most frequent haplotype in Argentina was associated with a lower %MMA and a higher percentage of DMA. Four polymorphisms in the DNMT genes were associated with metabolite patterns in Bangladesh. Noncoding AS3MT polymorphisms affected gene expression of AS3MT in peripheral blood, demonstrating that one functional impact of AS3MT polymorphisms may be altered levels of gene expression.ConclusionsPolymorphisms in AS3MT significantly predicted As metabolism across these two very different populations, suggesting that AS3MT may have an impact on As metabolite patterns in populations worldwide.

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Functional characterization of the schizophrenia associated gene AS3MT identifies a role in neuronal development.

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Functional characterization of the schizophrenia associated gene AS3MT identifies a role in neuronal development.

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