Implication of SSAT by Gene Expression and Genetic Variation in Suicide and Major Depression

McGill Group for Suicide Studies, Douglas Hospital, McGill University, Montreal, Quebec, Canada.
Archives of General Psychiatry (Impact Factor: 14.48). 01/2006; 63(1):35-48. DOI: 10.1001/archpsyc.63.1.35
Source: PubMed


A large body of evidence suggests that predisposition to suicide, an important public health problem, is mediated to a certain extent by neurobiological factors.
To investigate patterns of expression in suicide with and without major depression and to identify new molecular targets that may play a role in the neurobiology of these conditions.
Brain gene expression analysis was performed using the Affymetrix HG-U133 chipset in the orbital cortex (Brodmann area [BA] 11), the dorsolateral prefrontal cortex (BA8/9), and motor cortex (BA4). Subsequent studies were carried out in independent samples from adjacent areas to validate positive findings, confirm their relevance at the protein level, and investigate possible effects of genetic variation.
We investigated 12 psychiatrically normal control subjects and 24 suicide victims, including 16 with and 8 without major depression, in the brain gene expression analysis, validation, and protein studies. The genetic studies included 181 suicide completers and 80 psychiatrically normal controls. All subjects investigated were male and of French Canadian origin.
Gene expression measures from microarray, semiquantitative reverse transcription-polymerase chain reaction, immunohistochemistry, and Western blot analyses.
Twenty-six genes were selected because of the consistency of their expression pattern (fold change, >1.3 in either direction [P<or=.01] in at least 2 regions). The spermine/spermidine N(1)-acetyltransferase gene (SSAT) was successfully validated by reverse transcription-polymerase chain reaction, immunohistochemistry, and Western blot analyses. A variant located in the SSAT polyamine-responsive element regulatory region (SSAT342A/C) demonstrated a significant effect of genotype on SSAT brain expression levels (F(1) = 5.34; P = .02). Further investigation of this variant in an independent sample of 181 male suicide completers and 80 male controls showed a higher frequency of the SSAT342C allele among suicide cases (odds ratio, 2.7; 95% confidence interval, 1.4-5.3; P = .005), suggesting that this allele may increase predisposition to suicide.
These data suggest a role for SSAT, the rate-limiting enzyme in the catabolism of polyamines, in suicide and depression and a role for the SSAT342 locus in the regulation of SSAT gene expression.

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Available from: Adolfo Sequeira
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    • "Hypoxia is also unlikely to account for increase expression in the HC, since only sudden death controls were included. Despite accumulating evidence implicating SAT1 in depression and/ or suicide (Sequeira et al., 2006; Fiori et al., 2009, 2010; Guipponi et al., 2009; Klempan et al., 2009b; Fiori and Turecki, 2010a,b, 2011; Le-Niculescu et al., 2013; Lopez et al., 2014) including the current report , the mechanistic relationship between SAT1 expression, polyamine contents with depression and suicide remains unclear. Constitutively lower brain SAT1 expression in MDD could either be a result of, or directly contribute to, maladaptive polyamine stress response (PSR) during chronic stress (Gilad and Gilad, 2003). "
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    ABSTRACT: Low brain expression of the spermidine/spermine N-1 acetyltransferase (SAT1) gene, the rate-limiting enzyme involved in catabolism of polyamines that mediate the polyamine stress response (PSR), has been reported in depressed suicides. However, it is unknown whether this effect is associated with depression or with suicide and whether all or only specific isoforms expressed by SAT1, such as the primary 171 amino acid protein-encoding transcript (SSAT), or an alternative splice variant (SSATX) that is involved in SAT1 regulated unproductive splicing and transcription (RUST), are involved. We applied next generation sequencing (RNA-seq) to assess gene-level, isoform-level, and exon-level SAT1 expression differences between healthy controls (HC, N=29), DSM-IV major depressive disorder suicides (MDD-S, N=21) and MDD non-suicides (MDD, N=9) in the dorsal lateral prefrontal cortex (Brodmann Area 9, BA9) of medication-free individuals postmortem. Using small RNA-seq, we also examined miRNA species putatively involved in SAT1 post-transcriptional regulation. A DSM-IV diagnosis was made by structured interview. Toxicology and history ruled out recent psychotropic medication. At the gene-level, we found low SAT1 expression in both MDD-S (vs. HC, p=0.002) and MDD (vs. HC, p=0.002). At the isoform-level, reductions in MDD-S (vs. HC) were most pronounced in four transcripts including SSAT and SSATX, while reductions in MDD (vs. HC) was pronounced in three transcripts, one of which was reduced in MDD relative to MDD-S (all p<0.1 FDR corrected). We did not observe evidence for differential exon-usage (i.e. splicing) nor differences in miRNA expression. Results replicate the finding of low SAT1 brain expression in depressed suicides in an independent sample and implicate low SAT1 brain expression in MDD independent of suicide. Low expression of both SSAT and SATX isoforms suggest shared transcriptional mechanisms involved in RUST may account for low SAT1 brain expression in depressed suicides. Future studies are required to understand the functions and regulation of SAT1 isoforms, and how they relate to the pathogenesis of MDD and suicide. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · May 2015 · Neurobiology of Disease
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    • "ARTICLE promoter (Sequeira et al., 2006; Fiori et al., 2009). With respect to SMOX, regulatory genetic variants and epigenetic mechanisms do not seem to explain the lower expression levels observed in suicide (Fiori and Turecki, 2010c). "
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    ABSTRACT: MicroRNAs (miRNAs) are small, non-coding RNA molecules that play an important role in the post-transcriptional regulation of mRNA. These molecules have been the subject of growing interest as they are believed to control the regulation of a large number of genes, including those expressed in the brain. Evidence suggests that miRNAs could be involved in the pathogenesis of neuropsychiatric disorders. Alterations in metabolic enzymes of the polyamine system have been reported to play a role in predisposition to suicidal behaviour. We have previously shown the expression of the polyamine genes SAT1 and SMOX to be down-regulated in the brains of suicide completers. In this study, we hypothesized that the dysregulation of these genes in depressed suicide completers could be influenced by miRNA post-transcriptional regulation. Using a stringent target prediction analysis, we identified several miRNAs that target the 3'UTR of SAT1 and SMOX. We profiled the expression of 10 miRNAs in the prefrontal cortex (BA44) of suicide completers (N = 15) and controls (N = 16) using qRT-PCR. We found that several miRNAs showed significant up-regulation in the prefrontal cortex of suicide completers compared to psychiatric healthy controls. Furthermore, we demonstrated a significant correlation between these miRNAs and the expression levels of both SAT1 and SMOX. Our results suggest a relationship between miRNAs and polyamine gene expression in the suicide brain, and postulate a mechanism for SAT1 and SMOX down-regulation by post-transcriptional activity of miRNAs.
    Full-text · Article · Sep 2013 · The International Journal of Neuropsychopharmacology
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    • "Spermidine/spermine N1-acetyltranserare 1 (SAT1) is the key regulator of cellular polyamine content and is involved in the catabolism of spermidine and spermine, a key step in the maintenance of polyamine homeostasis (Pegg, 2008). Recently, Sequeira et al. (2006) showed a significant lower expression of SAT1 in multiple brain regions of suicide completers with and without depression compared to controls. The same finding was reported by further post-mortem studies in suicide (Sequeira et al., 2007; Guipponi et al., 2009; Klempan et al., 2009; Fiori et al., 2011) also showing altered expression for other polyamine system genes (Fiori et al., 2011). "
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    ABSTRACT: An altered polyamine system has been suggested to play a key role in mood disorders and suicide, a hypothesis corroborated by the evidence that lithium inhibits the polyamine mediated stress response in the rat brain. Recent post-mortem studies have shown that spermidine/spermine N1-acetyltransferase (SAT1), the key regulator of cellular polyamine content, is under-expressed in brains from suicide victims compared to controls. In our study we tested the effect of in vitro lithium treatment on SAT1 gene and protein expression in B lymphoblastoid cell lines (BLCLs) from bipolar disorder (BD) patients who committed suicide (and for which BLCLs were collected prior to their death), BD patients with high and low risk of suicide and a sample of non-psychiatric controls. Baseline mRNA levels were similar in the four groups of subjects (p > 0.05). Lithium had no effect in suicide completers (p > 0.05) while it significantly increased SAT1 expression in the high risk (p < 0.001) and low risk (p < 0.01) groups as well as in controls (p < 0.001). Protein and mRNA levels were not correlated; lithium significantly reduced protein levels only in the control sample (p < 0.05). Our findings suggest that SAT1 transcription is influenced by lithium and that this effect is altered in BD patients who completed suicide, further supporting a role for polyamines in suicide.
    Full-text · Article · Jun 2013 · The International Journal of Neuropsychopharmacology
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