Global gene expression profiling of the polyamine system in suicide completers

McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada.
The International Journal of Neuropsychopharmacology (Impact Factor: 4.01). 06/2011; 14(5):595-605. DOI: 10.1017/S1461145710001574
Source: PubMed


In recent years, gene expression, genetic association, and metabolic studies have implicated the polyamine system in psychiatric conditions, including suicide. Given the extensive regulation of genes involved in polyamine metabolism, as well as their interconnections with the metabolism of other amino acids, we were interested in further investigating the expression of polyamine-related genes across the brain in order to obtain a more comprehensive view of the dysregulation of this system in suicide. To this end, we examined the expression of genes related to polyamine metabolism across 22 brain regions in a sample of 29 mood-disordered suicide completers and 16 controls, and identified 14 genes displaying differential expression. Among these, altered expression of spermidine/spermine N1-acetyltransferase, spermine oxidase, and spermine synthase, has previously been observed in brains of suicide completers, while the remainder of the genes represent novel findings. In addition to genes with direct involvement in polyamine metabolism, including S-adenosylmethionine decarboxylase, ornithine decarboxylase antizymes 1 and 2, and arginase II, we identified altered expression of several more distally related genes, including aldehyde dehydrogenase 3 family, member A2, brain creatine kinase, mitochondrial creatine kinase 1, glycine amidinotransferase, glutamic-oxaloacetic transaminase 1, and arginyl-tRNA synthetase-like. Many of these genes displayed altered expression across several brain regions, strongly implying that dysregulated polyamine metabolism is a widespread phenomenon in the brains of suicide completers. This study provides a broader view of the nature and extent of the dysregulation of the polyamine system in suicide, and highlights the importance of this system in the neurobiology of suicide.

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    • "However, research is this field has just begun, and more experiments are necessary to clarify if hArg is just a suitable marker or a causal mediator in cerebrovascular disease (Atzler et al. 2015). A strong downregulation of the hArg synthesizing enzyme, AGAT, was found in mood-disordered suicide completers, which might be a first hint for a possible role of decreased hArg in the pathophysiology of neuropsychiatric disorders (Fiori et al. 2011). Surely, this conjecture remains a speculation until Fig. 1 Cellular localization of hCAT1, hCAT2 and hCAT3 in the adult human brain. "
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    ABSTRACT: L-Homoarginine is a cationic amino acid derivative, which is structurally related to L-arginine and lysine. Several lines of evidence point to nervous tissue as an important target of homoarginine action. In the mammalian brain homoarginine can be detected in noticeable quantities, but its origin is currently poorly explored. In part I of this review we try to show that both uptake and transport into brain (carried out by cationic amino acid transporters) and local synthesis in the brain (carried out by the homoarginine-synthesizing enzymes L-arginine:glycine amidinotransferase and ornithine transcarbamylse) might contribute to homoarginine brain content. We then give a brief overview about the multiple effects of homoarginine on the healthy brain and show that both homoarginine excess and deficiency are potentially harmful to the central nervous system. In part II, we shortly report about own experiments with regard to the cellular localization of cationic amino acid transporters, as well the enzymes L-arginine:glycine amidinotransferase and ornithine transcarbamylse, in human and rat brains.
    Amino Acids 03/2015; 47(9). DOI:10.1007/s00726-015-1960-y · 3.29 Impact Factor
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    • "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). These data provide additional evidence for the involvement of altered polyamine homeostasis in suicide. "
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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.
    The International Journal of Neuropsychopharmacology 06/2013; 16(10):1-10. DOI:10.1017/S1461145713000655 · 4.01 Impact Factor
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    • "Post-mortem brain tissue from BA44, which has been previously shown to demonstrate altered levels of polyamine genes in suicides (Fiori et al., 2011a), was obtained from the Quebec Suicide Brain Bank. Tissue was dissected at 4 C, snap-frozen in liquid nitrogen, and stored at À80 C following standard procedures. "
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    ABSTRACT: Suicide is among the leading causes of death worldwide. The polyamine system has been increasingly implicated in the neurobiology of suicide. Previous research has indicated that epigenetic mechanisms play a role in explaining dysregulation of polyamine genes in suicide completers. Nevertheless, regulatory mechanisms explaining polyamine biosynthetic genes displaying dysregulated expression in suicide completers, including ornithine decarboxylase antizymes 1 and 2 (OAZ1 and OAZ2), S-adenosylmethionine decarboxylase (AMD1), and arginase 2 (ARG2), have yet to be elucidated. In this study, we investigated methylation patterns in the promoter region of OAZ1, OAZ2, AMD1, and ARG2 in Brodmann area 44 from a group of 33 suicide completers and 31 non-suicide controls. We found significant site-specific differences in methylation in the promoter of ARG2 and AMD1 that were also significantly negatively correlated with gene expression. These findings provide further support for a role for the involvement of epigenetic modifications in the regulation of genes associated with polyamine biosynthesis, and which may contribute to the complexity of suicidal behaviors.
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