SIRT1 Activates MAO-A in the Brain to Mediate Anxiety and Exploratory Drive

Libert, Sergiy; Pointer, Kelli B.; Bell, Eric L.; Das, Abhirup; Cohen, David S.; Asara, John M.; Kapur, Karen; Bergmann, Sven; Preisig, Martin; Otowa, Takeshi; Kendler, Kenneth S.; Chen, Xiangning; Hettema, John M.; Oord, Edwin J. van den; Rubio, Justin P.; Guarente, Leonard

doi:10.1016/j.cell.2011.10.054

Cited by 202 publications

(191 citation statements)

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“…gov/), thus our results may be due to other unknown SIRT1 functional variants in linkage disequilibrium with the one investigated in our study. Consistently, the position of this SNP is near other variants which have been associated with both mood [22,30] and anxiety disorders [24] , suggesting the relevance of this gene, and in particular of this gene area, in the field. A number of strengths, however, are worth noting.…”

Section: Discussionmentioning

confidence: 54%

“…Consistently, reduced SIRT (1, 2, and 6) mRNA expression was observed in peripheral blood cells of unipolar and bipolar depressed patients [11] , and other psychiatric disorders were associated with SIRT1 gene variants, such as anxiety disorders (rs10997870), panic disorders (rs12778366 and rs10997870), and social phobia (rs12778366) [24] . Anyway, the involvement of SIRTs in the pathophysiology of mood disorders and SB is largely unknown, and studies investigating specifically the associations among SIRT1 gene variants and SB are lacking.…”

Section: Introductionmentioning

confidence: 66%

“…Though to the best of our knowledge this single-nucleotide polymorphism (SNP) does not show any direct functional effects, we decided to investigate this variant because of the previous association reported among this SNP and anxiety symptoms [24] , which are known to be related to SB in mood disorders [28,29] . Further, variants relatively near rs10997870 have recently been associated with mood disorder [22] -also in a large, whole-genome study [30] -, suggesting this gene region as worthy of further investigations in the field.…”

Section: Introductionmentioning

confidence: 99%

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Association between Sirtuin 1 Gene rs10997870 Polymorphism and Suicide Behaviors in Bipolar Disorder

et al. 2016

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Background/Aims: Suicidal behavior (SB) in bipolar disorder (BD) is a complex multifactorial event resulting from an interaction of genetic, neurobiological and psychosocial factors. Recent studies identified new possible mechanisms, suggesting a role for sirtuins (SIRTs 1-7), a family of nicotinamide adenine dinucleotide-dependent enzymes with a multifaceted role in the central nervous system. The aims of the present study were: (1) to investigate the effects of the rs10997870 SIRT1 gene variant on SB in BD; (2) to explore the effects of the same gene variant on specific depressive symptoms at the severest episode. Methods: One hundred and eighty DSM-IV bipolar outpatients were enrolled in a naturalistic cohort study. The rs10997870 polymorphism within the SIRT1 gene was analyzed. Results: An association between the GG genotype and SB was detected (lifetime: p = 0.015). Compared to other genotypes, GG carriers presented more frequently psychomotor agitation (p = 0.009) and a higher Hamilton Depression Rating Scale total score (p = 0.014) at the severest depressive episode. SB and psychomotor agitation were found to be associated with GG carriers and G allele in a multivariate analysis as well. Conclusion: Our findings suggest a role of the rs10997870 SIRT1 gene variant in SB amongst BD patients and its association with specific depressive symptoms. Despite a number of limitations of this exploratory study, our results may provide new insight into the mechanisms underlying SB in BD.

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Section: Discussionmentioning

confidence: 54%

Section: Introductionmentioning

confidence: 66%

Section: Introductionmentioning

confidence: 99%

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Association between Sirtuin 1 Gene rs10997870 Polymorphism and Suicide Behaviors in Bipolar Disorder

et al. 2016

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“…Фармакологические препараты, модулирующие уро-вень некодирующих РНК, которые участвуют в сиг-нальных путях контроля нейрогенеза (let-7, miR-30, miR-124, miR-16, miR-134) в клетках прилежащего ядра и гиппокампа, уменьшают степень выраженно-сти стресс-индуцированных депрессивных состояний [136,[148][149][150].…”

Section: Genetic Basis Of Ecosystems Evolutionunclassified

Genome and stress-reaction in animals and humans

Dyuzhikova

Алековна²,

Даев

et al. 2018

Ecological genetics

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Current data on the effects of stress at the level of the cell genomes of the central nervous system and peripheral organs in animals are discussed. Regulatory and structural genomic changes in the cells of the central nervous system under stress are considered as a mechanism for regulating the functions of the brain and peripheral organs that form the organism manifestations of stress. Based on the Yu.Ya. Kerkis and M.E. Lobashev point of view, we consider stress as a special physiological state of the nervous system, affecting the work and integrity of the genome in target cells in animals, and thus playing a major role in microevolutionary transformations.

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“…In the brain, Sirt1 regulates a number of transcriptional factors, such as the tumor suppressor p53, the Forkhead box O (FOXO) family, and nuclear factor-jB (NF-jB), as well as retinoic acid receptor b (RARb) and tau, and is thereby involved in regulation of cell survival, proliferation, and response to stress (Gan and Mucke 2008;Donmez and Outeiro 2013). In mice, overexpressed Sirt1 activated MAO-A transcription, reduced 5-HT and NE levels, and enhanced anxiety and exploratory drive, whereas Sirt1-knockout mice exhibited lower brain MAO-A levels (Libert et al 2011). Sirt1 binds the mao-a promoter in close proximity to the ATG start codon, and deacetylates the brain-specific nescient helix loop helix transcription factor 2 (NHLH2), activating the mao-a promoter; physical interaction of Sirt1 with NHLH2 has been shown by co-precipitation from mouse brain lysate.…”

Section: Modification Of Mao Expression By Environmental and Genetic mentioning

confidence: 99%

Modulation of monoamine oxidase (MAO) expression in neuropsychiatric disorders: genetic and environmental factors involved in type A MAO expression

2015

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Monoamine oxidase types A and B (MAO-A, MAO-B) regulate the levels of monoamine neurotransmitters in the brain, and their dysfunction may be involved in the pathogenesis and influence the clinical phenotypes of neuropsychiatric disorders. Reversible MAO-A inhibitors, such as moclobemide and befloxatone, are currently employed in the treatment of emotional disorders by inhibiting the enzymatic degradation of dopamine, serotonin and norepinephrine in the central nervous system (CNS). It has been suggested that the irreversible MAO-B inhibitors selegiline and rasagiline exert a neuroprotective effect in Parkinson's and Alzheimer's diseases. This effect, however, is not related to their inhibition of MAO activity; in animal and cellular models, selegiline and rasagiline protect neuronal cells through their anti-apoptotic activity and induction of pro-survival genes. There is increasing evidence that MAO-A activity, but not that of MAO-B, is implicated in the pathophysiology of neurodegenerative disorders, but also in gene induction by MAO-B inhibitors; on the other hand, selegiline and rasagiline increase MAO-A mRNA, protein, and enzyme activity levels. Taken together, these results suggest that each MAO subtype exerts effects that modulate the expression and activity of the other isoenzyme. The roles of MAO-A and -B in the CNS should therefore be re-evaluated with respect to the "type-specificity" of their inhibitors, which may not be unconditional during chronic treatment. Mao-a expression, in particular, may be implicated in pathogenesis and phenotypes in neuropsychiatric disorders. MAO-A expression is modified by mao polymorphisms affecting its transcriptional efficiency, as well as by mutations and polymorphism of parkin, Sirt1, FOXO, microRNA, presenilin-1, and other regulatory proteins. In addition, childhood maltreatment has been shown to have an impact upon adolescent social behavior in children with mao-a polymorphisms of low transcriptional activity. Low MAO-A activity may increase the levels of serotonin and norepinephrine, resulting in disturbed neurotransmitter system development and behavior. This review discusses genetic and environmental factors involved in the regulation of MAO-A expression, in the contexts of neuropsychiatric function and of the regulation of neuronal survival and death.

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SIRT1 Activates MAO-A in the Brain to Mediate Anxiety and Exploratory Drive

Cited by 202 publications

References 40 publications

Association between Sirtuin 1 Gene rs10997870 Polymorphism and Suicide Behaviors in Bipolar Disorder

Association between Sirtuin 1 Gene rs10997870 Polymorphism and Suicide Behaviors in Bipolar Disorder

Genome and stress-reaction in animals and humans

Modulation of monoamine oxidase (MAO) expression in neuropsychiatric disorders: genetic and environmental factors involved in type A MAO expression

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