Structure and promoter organization of the human monoamine oxidase A and B genes.

Monoamine oxidase (MAO) A and B play an important role in regulating levels of biogenic amines. MAO A and B cDNAs have been cloned and the deduced amino acids share 73% sequence identity. The genes for MAOA and B are comprised of 15 exons interspersed by 14 introns, span at least 60 kb and exhibit identical exon-intron organization. These findings suggest that the MAOA and MAOB genes are derived from the duplication of a common ancestral gene. The core promoter region of MAOA is comprised of two 90 bp repeats, each of which contains two Spl elements and lacks a TATA box. The MAOB core promoter region contains two sets of overlapping Spl sites which flank a CACCC element all upstream of a TATA box. The different organization of the MAOA and MAOB promoters may underlie their different cell and tissue specific expression.     

Personality correlates of platelet monoamine oxidase (MAO) activity in female and male subjects

Associations between platelet monoamine oxidase (MAO) activity and scale scores from the Eysenck Personality Questionnaire, the Impulsiveness-Venturesomeness-Empathy inventory and the Karolinska Scales of Personality were studied in 32 female and 29 male students (age range 17-19 years). There were significant negative correlations between MAO activity and extraversion-related scales for male subjects; in the female group the correlations were also negative but nonsignificant. When comparing subgroups with low, intermediate, and high platelet MAO activity subjects, consistent trends were observed in the direction of higher scores in the impulsivity scales, the sensation seeking-related Monotony avoidance scale, and the Indirect Aggression scale for both female and male low MAO activity groups.     

Brain monoamine oxidase (MAO) B: a unique neurotoxin and neurotransmitter producing enzyme

The notion that monoamine oxidase (MAO) functions solely to inactivate neurotransmitter and other biogenic amines needs to be re-evaluated. It is now apparent that MAO-B is capable of oxidizing inert non-polar amines such as MPTP (N-methyl-4-phenyl-1,2,3,6, tetrahydropyridine) and milacemide (2-n-pentylaminoacetamide) into neuroactive substances giving rise to Parkinson inducing dopaminergic neurotoxin, MPP+ and inhibitory amino acid neurotransmitter, glycine respectively. These findings accord new prospectives for neuropsychotherapy with selective MAO-B inhibitors and substrates.     

Similar distribution of monoamine oxidase (MAO) and parkinsonian toxin (MPTP) binding sites in human brain

1-Methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) causes parkinsonism in humans and other species. We found [3H] MPTP binding sites that were saturable, specific, and of high affinity. In autoradiographic studies, the highest binding densities of [3H] MPTP occurred in the hypothalamus, interpeduncular nucleus, and ependymal lining of the ventricles. High to moderate binding was seen in the dentate gyrus, caudate, putamen, substantia nigra, and cingulate cortex. The distribution of [3H] MPTP binding correlated with the distribution of [3H] pargyline binding to MAO. Human substantia nigra contains more MPTP binding sites than rat substantia nigra, and this may explain the sensitivity of humans to the neurotoxic effects of MPTP.     

Platelet monoamine oxidase B activity in parkinsonian patients.

Monoamine oxidase B (MAO B) plays a pivotal role in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced Parkinsonism. An increased MAO B activity in platelets of patients with idiopathic Parkinson's disease (PD) is reported in this study. The possibility that high MAO B activity may represent a trait of vulnerability for PD by enhancing the neurotoxic effects of environmental compounds is discussed.     

Progress in monoamine oxidase (MAO) research in relation to genetic engineering

Monoamine oxidase (MAO) is an enzyme that oxidizes various physiologically and pathologically important monoamine neurotransmitters and hormones such as dopamine, noradrenaline, adrenaline, and serotonin. Two types of MAO, i.e. type A (MAO-A) and type B (MAO-B), were first discovered pharmacologically. MAO-A is inhibited by clorgyline; and MAO-B, by deprenyl. cDNAs MAO-A and MAO-B were cloned and their structures determined. MAO-A and MAO-B are made of similar but different polypeptides and encoded by different nuclear genes located on the X chromosome (Xp11.23). MAO-A and MAO-B genes consist of 15 exons with identical intron-exon organization, suggesting that they were derived from a common ancestral gene. Both enzymes require a flavin cofactor, flavin adenine dinucleotide (FAD), which binds to the cysteine residue of a pentapeptide sequence (Ser-Gly-Gly-Cys-Tyr). Both enzymes exist on the outer membrane of mitochondria of various types of cells in various tissues including the brain. In humans, MAO-A is abundant in the brain and liver, whereas the liver, lungs and intestine are rich in MAO-B. MAO-A oxidizes noradrenaline and serotonin; and MAO-B, mainly beta-phenylethylamine. In the human brain, MAO-A exists in catecholaminergic neurons, but MAO-B is found in serotonergic neurons and glial cells. MAO-A knockout mice exhibit increased serotonin levels and aggressive behavior, whereas MAO-B knockout mice show little behavioral change. The gene knockout mice of MAO-A or MAO-B, together with the observation that some humans lack MAO-A, MAO-B, or both have contributed to our understanding of the function of MAO-A and MAO-B in health and disease. MAO-A and MAO-B may be closely related to various neuropsychiatric disorders such as depression and Parkinson's disease, and inhibitors of them are the subject of drug development for such diseases.     

Brain gamma-aminobutyrate aminotransferase (GABA-T) and monoamine oxidase (MAO) in patients with Alzheimer's disease

Summary Activities of Gamma-aminobutyrate aminotransferase (GABA-T) and Monoamine oxidase (MAO)-A and-B were estimated in postmortem brains from 6 control subjects without psychiatric or neurologic disorders and 8 histopathologically verified cases of patients with Alzheimer's disease and senile dementia of Alzheimer type (AD/SDAT). The enzyme activities were examined in four cortical brain regions, three nuclei in the basal ganglia, thalamus and white matter. GABA-T activities in the cortical regions (frontal, parietal, occipital and temporal cortices) and nucleus caudatus were significantly lowered in the AD/SDAT patients. The MAO-A activities were significantly increased in the occipital cortex, caudate nucleus, thalamus and white matter in the AD/SDAT patients. No significant differences were found in the other regions (frontal cortex, parietal cortex, temporal cortex, putamen and globus pallidus). The MAO-B activities in three cortical regions (frontal, parietal and occipital cortices), thalamus and white matter were significantly increased in the AD/SDAT patients, whereas no difference was apparent in the other regions. The changed activities could not be correlated with age or postmortem time. The present results are the first describing decreased GABA-T activities as well as increased MAO-A activities in brain from patients with AD/SDAT, while the results with MAO-B support previous findings. A possible connection was found between the order of magnitude of the changes in enzyme activities and the severity of the disease.     

Platelet monoamine oxidase B activity in Parkinson's disease: A re-evaluation

Summary An increase in platelet monoamine oxidase (MAO) B activity in drug-free parkinsonians (n=6) compared with healthy controls (n=10) has been confirmed using both phenylethylamine (PEA) and dopamine as substrates, reaching statistical, significance in the case of PEA oxidising activity (p<0.05). Thus, certain reports of raised platelet MAO B activity towards PEA but decreased activity towards dopamine in parkinsonians, raising the possibility of the existence of an abnormal form of MAO B in this condition, cannot be supported.     

Platelet monoamine oxidase activity and headache.

Mean platelet monoamine oxidase activity was reduced compared with control values in groups of headache-free male (but not female) patients suffering from classical migraine and from tension headache. Mean activity in male cluster patients, headache free, both during acute and quiescent phases of their illness, was also notably reduced. Retesting some migraine subjects after up to four years, showed that low activity may be a persistent feature: the correlation coefficient for repeated assays was 0.91 (p less than 0.01). There was no relationship between platelet monoamine oxidase activity and history of dietary migraine. A subgroup of headache patients with permanently low monoamine oxidase activity values may have been defined.     

Immunocytochemical localization of serotonin, monoamine oxidase and assessment of monoamine oxidase activity in human dental pulp

In the present study serotonin (5-hydroxytryptamine, 5-HT) and monoamine oxidase (MAO) were both found localized in the blood vessel walls of human dental pulp. Our discovery of MAO activity in human dental pulp suggests a functional relationship between serotonin and MAO in this region.     

Platelet monoamine oxidase activity in epilepsy.

The platelet monoamine oxidase activity (MAO) of 33 patients with epilepsy was compared with a group of neurological patients and a group of normal control subjects. We found that the MAO activity was increased significantly in the epileptic group when compared with the normal. This was not related to anticonvulsant medication. These results could be explained by the effect of epilepsy or anticonvulsant medication on the maturation of platelets.     

Distribution of type A and type B monoamine oxidase activity in hypothalamic nuclei of the rat.

The regional distribution of type A, type A and B and type B activity of monoamine oxidase (MAO) in individual nuclei of the rat hypothalamus was studied according to quantitative micromethods with clorgyline as a specific inhibitor of type A MAO. As results, type A and type B MAO were distributed differently in the rat hypothalamus. It is suggested that type B MAO acts differently from type A MAO in regard to the function of the hypothalamus.     

Immunological uniqueness of human monoamine oxidases A and B: new evidence from studies with monoclonal antibodies to human monoamine oxidase A

Monoamine oxidase (EC 1.4.3.4; MAO) is the primary enzyme responsible for the intraneuronal degradation of biogenic amines in the central nervous system. An understanding of the physiological significance of the functional and regulatory differences between the two forms of the enzyme, MAOs A and B, would be facilitated by the availability of antibodies specific for the two forms of the enzyme. We previously isolated and characterized a monoclonal antibody (MAO B-1C2, previously designated MAO-1C2) which binds human MAO B but not A. We describe here four new monoclonal antibodies (designated MAO A-3C9, A-4F10, A-7B10, and A-7E10) which were elicited to highly purified MAO A from human placenta and which, in the presence of antimouse IgG and Staphylococcus aureus, immunoprecipitate greater than 90% of the catalytically active purified MAO A. MAO A-3C9 appears to have a lower affinity for purified MAO A than the other three antibodies and does not immunoprecipitate either MAO A or MAO B from human platelets or from Triton X-100 extracts of human placental and liver mitochondria. MAO A-4F10, A-7B10, and A-7E10 immunoprecipitate catalytically active MAO A from Triton X-100 extracts of human placental and liver mitochondria, but not catalytically active MAO B from either pletelets or from Triton X-100 extracts of human liver mitochondria. Collectively, these anti-MAO monoclonal antibodies reveal unique epitopes on human MAO A not shared by MAO B, and at least one epitope on MAO B not shared by MAO A. These immunochemical differences support the hypothesis that MAO A and MAO B are different proteins, presumably isozymes.     

A commingling analysis of platelet monoamine oxidase activity

The distribution of platelet monoamine oxidase (MAO) activity is examined in a large cohort of 18-year-olds from a college setting. A mixture of three distributions is needed to describe the data, even when a power transformation is used to remove skewness in the distribution. This is compatible with MAO activity being controlled by a single major locus with a gene frequency of 0.02 for high-MAO activity. Accordingly, it is unlikely that such a locus could serve as a genetic marker for a disorder which is associated with low activity. However, this finding does not rule out the possibility that MAO activity is an associated risk factor in disease.     

Studies on biogenic amine metabolizing enzymes (DBH, COMT, MAO) and pathogenesis of affective illness. III. Platelet monoamine oxidase activity in endogenous depression

Platelet MAO activity was determined in blood from 31 healthy persons and 43 persons with endogenous depressive syndrome. It was found that the enzyme activity is significantly higher in women than in men, both in healthy controls and in affective illness groups. Statistically significant lowering of the enzyme activity was found in the group of women with affective illness as compared with healthy women controls (P less than 0.05). Although the latter phenomenon is true of all three diagnostic subgroups of affective disorder (bipolar, unipolar, undifferentiated), it is most pronounced, and statistically significant only in the group of women with an undifferentiated course of disease. A small rise in the enzyme activity was noticed in some patients during remission, as compared with a period of depression, but this was not statistically significant. Analysis of the possible links between MAO activity and the clinical picture, or the severity of depression, revealed no significant correlations. No correlation was found between the level of MAO activity and a family history of psychiatric disturbances in general, and affective disorders in particular--in either women or in men.     

Expression of monoamine oxidase B activity in astrocytes of senile plaques

Summary Monoamine oxidase (MAO) histochemistry has been performed in brains from patients with dementia of Alzheimer type (DAT) and aged controls. Conspicuous MAO-positive cell clusters were frequently observed in the amygdala, hippocampus, and insular cortex in the brains of DAT. Double staining with glial fibrillary acidic protein immunohistochemistry revealed that the clusterforming MAO-positive cells were astrocytes. Using Bielschowsky's method, Congo red and thioflavin S counterstaining, this astrocytic mass was shown to be associated with senile plaques. By the enzyme inhibition experiment, MAO activity in senile plaques was revealed to be of type B. The present results clearly indicate that MAO-B activity is expressed in fibrillary astrocytes in or around senile plaques, suggesting that these astrocytes metabolize exogenous amines in senile plaques.