MAOA
Amine oxidase [flavin-containing] A (EC 1.4.3.4) (Monoamine oxidase type A) (MAO-A)
Publications[править]
Catecholamine-induced lipolysis, the first step in the generation of energy substrates by the hydrolysis of triglycerides, declines with age. The defect in the mobilization of free fatty acids in the elderly is accompanied by increased visceral adiposity, lower exercise capacity, failure to maintain core body temperature during cold stress, and reduced ability to survive starvation. Although catecholamine signalling in adipocytes is normal in the elderly, how lipolysis is impaired in ageing remains unknown. Here we show that adipose tissue macrophages regulate the age-related reduction in adipocyte lipolysis in mice by lowering the bioavailability of noradrenaline. Unexpectedly, unbiased whole-transcriptome analyses of adipose macrophages revealed that ageing upregulates genes that control catecholamine degradation in an NLRP3 inflammasome-dependent manner. Deletion of NLRP3 in ageing restored catecholamine-induced lipolysis by downregulating growth differentiation factor-3 (GDF3) and monoamine oxidase A (MAOA) that is known to degrade noradrenaline. Consistent with this, deletion of GDF3 in inflammasome-activated macrophages improved lipolysis by decreasing levels of MAOA and caspase-1. Furthermore, inhibition of MAOA reversed the age-related reduction in noradrenaline concentration in adipose tissue, and restored lipolysis with increased levels of the key lipolytic enzymes adipose triglyceride lipase (ATGL) and hormone sensitive lipase (HSL). Our study reveals that targeting neuro-immunometabolic signalling between the sympathetic nervous system and macrophages may offer new approaches to mitigate chronic inflammation-induced metabolic impairment and functional decline.
MeSH Terms
- Adipocytes
- Adipose Tissue
- Aging
- Animals
- Caspase 1
- Catecholamines
- Gene Expression Profiling
- Gene Expression Regulation
- Growth Differentiation Factor 3
- Inflammasomes
- Lipase
- Lipolysis
- Macrophages
- Mice
- Monoamine Oxidase
- Monoamine Oxidase Inhibitors
- NLR Family, Pyrin Domain-Containing 3 Protein
- Norepinephrine
- Sterol Esterase
Little is known about the effects of risk factors on attention-deficit/hyperactivity disorder (ADHD) symptom over time. Here, we longitudinally studied the role of candidate genes, pre- and perinatal factors, and their interactions on ADHD symptoms between ages 10 and 18 years. Subjects were part of the general population or clinic-referred cohort of the TRacking Adolescents' Individual Lives Survey (n = 1667). At mean ages of 11.1 (T1), 13.4 (T2), and 16.2 years (T3), ADHD symptoms were assessed with the Child Behavior Checklist. Linear Mixed Models were used to examine the association of candidate genes (i.e., DRD4, DRD2, 5-HTTLPR, COMT, and MAOA), pre- and perinatal factors (i.e., index measure of various pregnancy and delivery complications, maternal smoking, maternal drinking, and low birth weight), and their interactions with ADHD symptoms across adolescence. Pregnancy and delivery complications were associated with a higher level of ADHD symptoms across all time points, but with a significantly declining influence over time (p = 0.006). We found no main effects of the candidate genes on ADHD symptoms throughout adolescence. The simultaneous presence of the low activity MAOA genotype and low birth weight (p < 0.001) and of the 5-HTTLPR LL-allele and respectively pregnancy and delivery complications (p = 0.04) and maternal smoking (p = 0.04) were associated with more ADHD symptoms particularly during early adolescence, and these influences significantly decreased over time. Findings suggest an age-dependent role of gene-environment interactions on ADHD symptoms across adolescence.
MeSH Terms
- Adolescent
- Aging
- Attention Deficit Disorder with Hyperactivity
- Child
- Female
- Gene-Environment Interaction
- Genotype
- Humans
- Male
- Monoamine Oxidase
- Polymorphism, Single Nucleotide
- Pregnancy
- Pregnancy Complications
- Prenatal Exposure Delayed Effects
- Psychiatric Status Rating Scales
- Serotonin Plasma Membrane Transport Proteins
Optimism and resilience promote health and well-being in older adults, and previous reports suggest that these traits are heritable. We examined the association of selected single-nucleotide polymorphisms (SNPs) with optimism and resilience in older adults. Candidate gene association study that was a follow-on at the University of California, San Diego, sites of two NIH-funded multi-site longitudinal investigations: Women's Health Initiative (WHI) and SELenium and vitamin E Cancer prevention Trial (SELECT). 426 women from WHI older than age 50 years, and 509 men older than age 55 years (age 50 years for African American men) from SELECT. 65 candidate gene SNPs that were judged by consensus, based on a literature review, as being related to predisposition to optimism and resilience, and 31 ancestry informative marker SNPs, genotyped from blood-based DNA samples and self-report scales for trait optimism, resilience, and depressive symptoms. Using a Bonferroni threshold for significant association (p = 0.00089), there were no significant associations for individual SNPs with optimism or resilience in single-locus analyses. Exploratory multi-locus polygenic analyses with p <0.05 showed an association of optimism with SNPs in MAOA, IL10, and FGG genes, and an association of resilience with a SNP in MAOA gene. Correcting for Type I errors, there were no significant associations of optimism and resilience with specific gene SNPs in single-locus analyses. Positive psychological traits are likely to be genetically complex, with many loci having small effects contributing to phenotypic variation. Our exploratory multi-locus polygenic analyses suggest that larger sample sizes and complementary approaches involving methods such as sequence-based association studies, copy number variation analyses, and pathway-based analyses could be useful for better understanding the genetic basis of these positive psychological traits.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Depression
- European Continental Ancestry Group
- Female
- Fibrinogens, Abnormal
- Genetic Association Studies
- Genotype
- Humans
- Interleukin-10
- Male
- Middle Aged
- Monoamine Oxidase
- Multifactorial Inheritance
- Personality
- Polymorphism, Single Nucleotide
- Resilience, Psychological
Keywords
- Optimism
- aging
- depression
- genotyping
- resilience
- single-nucleotide polymorphisms
Alzheimer's disease (AD) and depression (DE) are common psychiatric disorders strongly intertwined with one another. Nevertheless, etiology and early diagnosis of the disorders are still elusive. Several genetic variations have been suggested to associate with AD and DE, particularly in genes involved in the serotonergic system such as the serotonin transporter (SERT/SLC6A4), responsible for the removal from the synaptic cleft, and the monoamine-oxidase-A (MAOA), responsible for the presynaptic degradation of serotonin. Here, we attempt to characterize this pleiotropic effect for the triallelic SERT gene-linked polymorphic region (5HTTLPR) and for the MAOA-uVNTR, in participants in the Vienna-Transdanube-Aging (VITA)-study. The VITA-study is a community-based longitudinal study following a birth cohort (75 years old at baseline examination, n = 606) from Vienna for a period of 90 months with a regular follow-up interval of 30 months. Our main finding, confirming previous reports, is that the 5HTTLPR S-allele is a risk allele for DE (OR = 1.55 CI 95% 1.03-2.32) and its carriers had a steeper increase in SGDS sum score. No association to AD was found. MAOA-uVNTR did not associate with either AD or DE. However, in AD MAOA-uVNTR S-allele carriers a steeper increase of HAMD and STAI1 sum scores (P < 0.05) was observed. Although the VITA-study cohort is rather small with low power to detect gene alterations, the uniqueness of this very thoroughly investigated and homogenous cohort strengthens the results through exceptional data collection. Still, reinvestigation in a larger cohort similar to this, as well as a meta-analysis, is important to confirm these results.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Alzheimer Disease
- Depression
- Female
- Genotype
- Humans
- Longitudinal Studies
- Male
- Monoamine Oxidase
- Polymorphism, Genetic
- Serotonin Plasma Membrane Transport Proteins
Keywords
- Alzheimer's disease
- MAOA
- SLC6A4
- depression
- polymorphism
- serotonin transporter