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Journal ArticleDOI

Monoamine oxidase: from genes to behavior.

01 Jan 1999-Annual Review of Neuroscience (NIH Public Access)-Vol. 22, Iss: 1, pp 197-217
TL;DR: MAO A and B knock-out mice are valuable models for investigating the role of monoamines in psychoses and neurodegenerative and stress-related disorders and show increased reactivity to stress.
Abstract: Cloning of MAO (monoamine oxidase) A and B has demonstrated unequivocally that these enzymes are made up of different polypeptides, and our understanding of MAO structure, regulation, and function has been significantly advanced by studies using their cDNA. MAO A and B genes are located on the X-chromosome (Xp11.23) and comprise 15 exons with identical intron-exon organization, which suggests that they are derived from the same ancestral gene. MAO A and B knock-out mice exhibit distinct differences in neurotransmitter metabolism and behavior. MAO A knock-out mice have elevated brain levels of serotonin, norephinephrine, and dopamine and manifest aggressive behavior similar to human males with a deletion of MAO A. In contrast, MAO B knock-out mice do not exhibit aggression and only levels of phenylethylamine are increased. Mice lacking MAO B are resistant to the Parkinsongenic neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine. Both MAO A and B knock-out mice show increased reactivity to stress. These knock-out mice are valuable models for investigating the role of monoamines in psychoses and neurodegenerative and stress-related disorders.

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Citations
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Journal ArticleDOI
02 Aug 2002-Science
TL;DR: In this paper, a large sample of male children from birth to adulthood was studied to determine why some children who are maltreated grow up to develop antisocial behavior, whereas others do not.
Abstract: We studied a large sample of male children from birth to adulthood to determine why some children who are maltreated grow up to develop antisocial behavior, whereas others do not. A functional polymorphism in the gene encoding the neurotransmitter-metabolizing enzyme monoamine oxidase A (MAOA) was found to moderate the effect of maltreatment. Maltreated children with a genotype conferring high levels of MAOA expression were less likely to develop antisocial problems. These findings may partly explain why not all victims of maltreatment grow up to victimize others, and they provide epidemiological evidence that genotypes can moderate children's sensitivity to environmental insults.

4,151 citations

Journal ArticleDOI
TL;DR: The mechanism of mitochondrial RIRR highlights the central role of mitochondria-formed ROS, and all of the known ROS-producing sites and their relevance to the mitochondrial ROS production in vivo are discussed.
Abstract: Byproducts of normal mitochondrial metabolism and homeostasis include the buildup of potentially damaging levels of reactive oxygen species (ROS), Ca2+, etc., which must be normalized. Evidence suggests that brief mitochondrial permeability transition pore (mPTP) openings play an important physiological role maintaining healthy mitochondria homeostasis. Adaptive and maladaptive responses to redox stress may involve mitochondrial channels such as mPTP and inner membrane anion channel (IMAC). Their activation causes intra- and intermitochondrial redox-environment changes leading to ROS release. This regenerative cycle of mitochondrial ROS formation and release was named ROS-induced ROS release (RIRR). Brief, reversible mPTP opening-associated ROS release apparently constitutes an adaptive housekeeping function by the timely release from mitochondria of accumulated potentially toxic levels of ROS (and Ca2+). At higher ROS levels, longer mPTP openings may release a ROS burst leading to destruction of mitochondria, and if propagated from mitochondrion to mitochondrion, of the cell itself. The destructive function of RIRR may serve a physiological role by removal of unwanted cells or damaged mitochondria, or cause the pathological elimination of vital and essential mitochondria and cells. The adaptive release of sufficient ROS into the vicinity of mitochondria may also activate local pools of redox-sensitive enzymes involved in protective signaling pathways that limit ischemic damage to mitochondria and cells in that area. Maladaptive mPTP- or IMAC-related RIRR may also be playing a role in aging. Because the mechanism of mitochondrial RIRR highlights the central role of mitochondria-formed ROS, we discuss all of the known ROS-producing sites (shown in vitro) and their relevance to the mitochondrial ROS production in vivo.

2,893 citations


Cites background from "Monoamine oxidase: from genes to be..."

  • ...Paradoxically, the ablation of MAO causes a very slight rise of its endogenous substrates in the brain tissue (386)....

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Journal ArticleDOI
TL;DR: This work evaluates claims and some counter-claims made about the physiological importance of these enzymes and the potential of their inhibitors in the light of what the authors know, and still have to learn, of the structure, function and genetics of the monoamine oxidases and the disparate actions of their inhibitor.
Abstract: Monoamine oxidase inhibitors were among the first antidepressants to be discovered and have long been used as such. It now seems that many of these agents might have therapeutic value in several common neurodegenerative conditions, independently of their inhibition of monoamine oxidase activity. However, many claims and some counter-claims have been made about the physiological importance of these enzymes and the potential of their inhibitors. We evaluate these arguments in the light of what we know, and still have to learn, of the structure, function and genetics of the monoamine oxidases and the disparate actions of their inhibitors.

1,173 citations


Cites background from "Monoamine oxidase: from genes to be..."

  • ...Mitochondrial monoamine oxidases MAO catalyses the oxidative deamination of a range of monoamines, including 5-hydroxytryptamine (5-HT, or serotonin), histamine and the catecholamines dopamine, noradrenaline and adrenalin...

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Journal ArticleDOI
TL;DR: These findings provide the strongest evidence to date suggesting that the MAOA gene influences vulnerability to environmental stress, and that this biological process can be initiated early in life.
Abstract: Previous research on adults has shown that a functional polymorphism in the promoter region of the monoamine oxidase A (MAOA) gene moderates the impact of childhood maltreatment on risk for developing antisocial behavior. Thus far, attempts to replicate this finding have been mixed. The current study (i) presents new data investigating this finding in a sample of 975 seven-year-old boys, and (ii) evaluates the extant data by conducting a meta-analysis of published findings. We replicated the original finding by showing that the MAOA polymorphism moderates the development of psychopathology after exposure to physical abuse, we extended the finding to childhood closer in time to the maltreatment experience, and we ruled-out the possibility of a spurious finding by accounting for passive and evocative gene-environment correlation. Moreover, meta-analysis demonstrated that across studies, the association between maltreatment and mental health problems is significantly stronger in the group of males with the genotype conferring low vs high MAOA activity. These findings provide the strongest evidence to date suggesting that the MAOA gene influences vulnerability to environmental stress, and that this biological process can be initiated early in life.

1,083 citations

Journal ArticleDOI
TL;DR: It is revealed that approximately 85% of brain 2-AG hydrolase activity can be ascribed to MAGL, and that the remaining 15% is mostly catalyzed by two uncharacterized enzymes, ABHD6 and ABHD12.

1,031 citations


Cites background from "Monoamine oxidase: from genes to be..."

  • ...Indeed, the metabolism of other classes of bioactive molecules, including acetylcholine [41], monoamines [42], and prostaglandins [43], has been shown to be regulated by multiple enzymes or multiple isoforms of the same enzyme....

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References
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Journal ArticleDOI
27 Jun 1997-Science
TL;DR: A mutation was identified in the α-synuclein gene, which codes for a presynaptic protein thought to be involved in neuronal plasticity, in the Italian kindred and in three unrelated families of Greek origin with autosomal dominant inheritance for the PD phenotype.
Abstract: Parkinson's disease (PD) is a common neurodegenerative disorder with a lifetime incidence of approximately 2 percent. A pattern of familial aggregation has been documented for the disorder, and it was recently reported that a PD susceptibility gene in a large Italian kindred is located on the long arm of human chromosome 4. A mutation was identified in the α-synuclein gene, which codes for a presynaptic protein thought to be involved in neuronal plasticity, in the Italian kindred and in three unrelated families of Greek origin with autosomal dominant inheritance for the PD phenotype. This finding of a specific molecular alteration associated with PD will facilitate the detailed understanding of the pathophysiology of the disorder.

7,387 citations


"Monoamine oxidase: from genes to be..." refers background in this paper

  • ...A gene responsible for Parkinsonism has been identified in four unrelated families (Polymeropoulos et al 1997), indicating that familial Parkinson’s disease may be inherited....

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Journal ArticleDOI
TL;DR: In patients with moderately severe impairment from Alzheimer's disease, treatment with selegiline or alpha-tocopherol slows the progression of disease.
Abstract: Background There is evidence that medications or vitamins that increase the levels of brain catecholamines and protect against oxidative damage may reduce the neuronal damage and slow the progression of Alzheimer's disease. Methods We conducted a double-blind, placebo-controlled, randomized, multicenter trial in patients with Alzheimer's disease of moderate severity. A total of 341 patients received the selective monoamine oxidase inhibitor selegiline (10 mg a day), alpha-tocopherol (vitamin E, 2000 IU a day), both selegiline and alpha-tocopherol, or placebo for two years. The primary outcome was the time to the occurrence of any of the following: death, institutionalization, loss of the ability to perform basic activities of daily living, or severe dementia (defined as a Clinical Dementia Rating of 3). Results Despite random assignment, the base-line score on the Mini–Mental State Examination was higher in the placebo group than in the other three groups, and this variable was highly predictive of the pr...

2,357 citations


"Monoamine oxidase: from genes to be..." refers background in this paper

  • ...Indeed, patients with Parkinson’s disease have elevated MAO B activity in the substantia nigra (Riederer & Jellinger 1983), and the MAO B inhibitor, deprenyl, delays the progression of symptoms (Knoll 1988, Sano et al 1997)....

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  • ...Eight males from a Dutch family with a MAO A deficiency due to a point mutation in the gene encoding MAO A manifest abnormal aggressiveness (Brunner et al 1993a,b), and alterations in MAO B activity have been implicated in Parkinson’s disease (Hotamisligil et al 1994, Sano et al 1997)....

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  • ...The MAO B inhibitor, deprenyl, delays the progression of the symptoms of Parkinson’s disease (Knoll 1988, Sano et al 1997), and H2O2 generated during MAO-catalyzed oxidation of neurotransmitters may cause damage to mitochondrial DNA (Hauptmann et al 1996)....

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Journal ArticleDOI
TL;DR: The hypothesis that in the enzyme prepared, the MAO is a binary system of enzymes each of which has a detectably different sensitivity to this particular inhibitor, is put forward and evidence after dialysis supports this hypothesis.

1,557 citations


"Monoamine oxidase: from genes to be..." refers background in this paper

  • ...On the basis of substrate selectivity and inhibitor sensitivity, two forms of MAO were proposed and designated MAO A and B (Johnston 1968, Knoll & Magyar 1972)....

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  • ...Although in humans DA is oxidized by MAO B (Glover et al 1977) and in rodents it is oxidized by MAO A (Johnston 1968, Neff & Yang 1974), in most species DA can be oxidized by both forms of the enzymes (O’Carroll et al 1983)....

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  • ...Over two decades ago, Johnston defined two subtypes of MAO based on the observation that one form (A) but not the other (B) was sensitive to the irreversible inhibitor, clorgyline (Johnston 1968)....

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  • ...The discovery in 1968 of the two forms of MAO (Johnston 1968) raised a question: Are MAO A and B different proteins or the same protein differentially modified posttranslationally by carbohydrates or lipids?...

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Journal ArticleDOI
22 Oct 1993-Science
TL;DR: Analytical results indicate that isolated complete MAOA deficiency in this family is associated with a recognizable behavioral phenotype that includes disturbed regulation of impulsive aggression.
Abstract: Genetic and metabolic studies have been done on a large kindred in which several males are affected by a syndrome of borderline mental retardation and abnormal behavior. The types of behavior that occurred include impulsive aggression, arson, attempted rape, and exhibitionism. Analysis of 24-hour urine samples indicated markedly disturbed monoamine metabolism. This syndrome was associated with a complete and selective deficiency of enzymatic activity of monoamine oxidase A (MAOA). In each of five affected males, a point mutation was identified in the eighth exon of the MAOA structural gene, which changes a glutamine to a termination codon. Thus, isolated complete MAOA deficiency in this family is associated with a recognizable behavioral phenotype that includes disturbed regulation of impulsive aggression.

1,481 citations


"Monoamine oxidase: from genes to be..." refers background in this paper

  • ...Norrie disease is an X-linked recessive neurologic disorder characterized by blindness, hearing loss, and mental retardation (Brunner et al 1993a,b; Collins et al 1992)....

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  • ...Eight males from a Dutch family with a MAO A deficiency due to a point mutation in the gene encoding MAO A manifest abnormal aggressiveness (Brunner et al 1993a,b), and alterations in MAO B activity have been implicated in Parkinson’s disease (Hotamisligil et al 1994, Sano et al 1997)....

    [...]

  • ...The enhanced aggressive behavior exhibited by MAO A KO mice is consistent with the abnormal aggression reported in males from a Dutch family with a complete MAO A deficiency due to a point deletion in the gene encoding MAO A (Brunner et al 1993a)....

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Journal ArticleDOI
23 Jun 1995-Science
TL;DR: Pup behavioral alterations, including trembling, difficulty in righting, and fearfulness were reversed by the serotonin synthesis inhibitor parachlorophenylalanine, and adults manifested a distinct behavioral syndrome, including enhanced aggression in males.
Abstract: Deficiency in monoamine oxidase A (MAOA), an enzyme that degrades serotonin and norepinephrine, has recently been shown to be associated with aggressive behavior in men of a Dutch family. A line of transgenic mice was isolated in which transgene integration caused a deletion in the gene encoding MAOA, providing an animal model of MAOA deficiency. In pup brains, serotonin concentrations were increased up to ninefold, and serotonin-like immunoreactivity was present in catecholaminergic neurons. In pup and adult brains, norepinephrine concentrations were increased up to twofold, and cytoarchitectural changes were observed in the somatosensory cortex. Pup behavioral alterations, including trembling, difficulty in righting, and fearfulness were reversed by the serotonin synthesis inhibitor parachlorophenylalanine. Adults manifested a distinct behavioral syndrome, including enhanced aggression in males.

1,165 citations


"Monoamine oxidase: from genes to be..." refers background or result in this paper

  • ...Both MAO A–deficient mice (Cases et al 1995) and MAO B–deficient mice (Grimsby et al 1997) show an increased reactivity to stress in the forced-swim test....

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  • ...A (Cases et al 1995) is disrupted....

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  • ...An increase in MAO B activity with development is consistent with the finding that pups deficient in MAO A show higher levels of 5-HT and 5-HT immunoreactivity compared with adults (Cases et al 1995)....

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  • ...…their action is potentiated by PEA (Berry et al 1994 Dyck et al 1993, Juorio et al 1988, Paterson et al 1990, Scarr et al 1994, Yu et al 1994), these findings are consistent with elevated brain levels of NE and DA in MAO A KO mice (Cases et al 1995) and PEA in MAO B KO mice (Grimsby et al 1997)....

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  • ...In brains of MAO A KO pups and adults, NE concentrations were increased up to two-fold, and a small increase in DA levels was observed in pup brains (Cases et al 1995)....

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