Implication of SSAT by Gene Expression and Genetic Variation in Suicide and Major Depression
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.
- "Хотя функции ПА в мозге пока в значительной мере остаются загадкой [38, 51, 119, 184, 185, 189, 197, 198, 208, 212, 277, , сейчас становится очевидным, что ПА связаны с глиальными клетками. Измененный метаболизм ПА может лежать в основе расстройств мозга [44, 94], в том числе депрессии с суицидальнoй тенденцией . Истощение запаса эндогенного СПД/СПМ при определенной диете [96, 290] или при генной активации деградирующего СПМ фермента приводит к потере ПА и ухудшении резистентности нейронов к патологическим факторам [97, 98]. "
[Show abstract] [Hide abstract] 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.0Comments 2Citations
- "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 Fiori et al., , 2010 Guipponi et al., 2009; Klempan et al., 2009b; 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 ). "
[Show abstract] [Hide abstract] ABSTRACT: Major depressive disorder (MDD) is a serious health concern worldwide. Currently there are no predictive tests for the effectiveness of any particular antidepressant in an individual patient. Thus, doctors must prescribe antidepressants based on educated guesses. With the recent advent of scientific research, genome-wide gene expression microarray studies are widely utilized to analyze hundreds of thousands of biomarkers by high-throughput technologies. In addition to the candidate-gene approach, the genome-wide approach has recently been employed to investigate the determinants of MDD as well as antidepressant response to therapy. In this review, we mainly focused on gene expression studies with genome-wide approaches using RNA derived from peripheral blood cells. Furthermore, we reviewed their limitations and future directions with respect to the genome-wide gene expression profiling in MDD pathogenesis as well as in antidepressant therapy. Copyright © 2015. Published by Elsevier Inc.0Comments 3Citations
- "In their analysis for transcripts, about 200 candidate genes were identified as dysregulated when MDE patients were compared with controls (including the regulator of endothelin 1 (EDN1), ELK3 ETS-domain protein (ELK3), progestin and adipoQ receptor family member VI (PAQR6), protein phosphatase Mg2+/Mn2+ dependent 1K (PPM1K), and G-protein signaling 7 binding protein (RGS7BP) genes). The EDN1, ELK3, PAQR6, PPM1K, and RGS7BP genes have also been previously identified as dysregulated in brain tissues with MDD (Guilloux et al., 2012; Sequeira et al., 2006 Sequeira et al., , 2007). Belzeaux and colleagues also tested the hypothesis that gene expression profile (including mRNA and miRNA expression) can predict response to antidepressants with MDE patients (Belzeaux et al., 2012). "
Discover cutting-edge research
ResearchGate is where you can find and access the latest publications from your field of research.Discover more