Platelet monoamine oxidase activity is related to MAOB intron 13 genotype

Summary. Monoamine oxidases (MAO) play a critical role in the degradation of endogenous and exogenous amines throughout the body. There are two distinct MAO isoforms, MAO-A and MAO-B, which both are encoded in genes on the X chromosome. Alterations in MAO-B activity have previously been connected with several neurological disorders. Platelet MAO (trbc-MAO) is exclusively of the B-type and the catalytic activity of this enzyme is under strong, yet unknown, genetic control. Specific trbc-MAO activity has been reported to be increased in certain neurodegenerative diseases and to correlate with personality traits such as sensation seeking and impulsiveness. In the present study, we investigated if trbc-MAO activity is associated with genotype at a variable region (A/G dimorphism) in intron 13 of the human gene encoding MAO-B. The MAOB intron 13 allele status and levels of trbc-MAO were determined for 55 Caucasian non-smoking males. Individuals with the "A-allele" displayed significantly lower enzyme activity than individuals with the "G-allele", i.e. 11.4 ± 0.6 nmol/10¹⁰ platelets/min compared with 13.5 ± 0.6 (mean ± SEM, p = 0.019). The present results suggest that the MAOB genotype may be involved in determining trbc-MAO activity. Received July 1, 1999; accepted January 11, 2000     

单胺氧化酶B基因13内含子G/A多态性与帕金森病的关系

目的探讨多巴胺代谢酶———单胺氧化酶B(MAO-B)基因13内含子G/A多态性与帕金森病(PD)的关系。方法应用PCR-限制性片段长度多态性(RFLP)技术检测166例PD患者(其中早发型52例,晚发型114例)和170名正常对照者的MAO-B基因13内含子G/A位点的基因型和等位基因,比较分析其分布情况。结果 PD组与正常对照组MAO-B基因野生型(AA)、杂合型(AG)、突变型(GG)频率及等位基因频率差异无统计学意义;PD早发型亚组的AA型(80.8%)和A等位基因型频率(86.5%)显著高于晚发型亚组(60.5%,71.5%)及正常对照组(60.6%,71.5%)(均P<0.05);PD晚发型亚组与正常对照组各基因型和等位基因频率的差异无统计学意义;PD男性及女性亚组与同性别正常对照组的基因型和等位基因频率的差异均无统计学意义。结论 MAO-B基因13内含子AA型和A等位基因频率增高是PD发病的危险因素之一;MAO-B基因13内含子G/A多态性与PD,尤其是与早发型PD的遗传易感性有关。     

Platelet monoamine oxidase B and plasma beta-phenylethylamine in Parkinson's disease

OBJECTIVE: To evaluate the correlation between changes in platelet monoamine oxidase type B (MAO-B) activity and plasma beta-phenylethylamine (PEA) concentrations in patients with Parkinson's disease and controls. METHODS: Platelet MAO-B activity and plasma PEA were measured with gas chromatography-mass spectrometry (GC-MS) in patients with Parkinson's disease treated with levodopa (12 men and 12 women) or selegiline (three men and three women), and physically healthy subjects as a control group (10 men and 10 women). RESULTS: Platelet MAO-B activity was significantly higher in the Parkinson's disease group (mean 542 (SD 318) pmol/10(7) platelets/30 min) than in the control group (mean 349 (SD 307) pmol/10(7) platelets/30 min) (p<0.05). By contrast, the plasma PEA concentrations in patients with Parkinson's disease were significantly lower than in the control group (mean 532 (SD 243) pg/ml; 931 (SD 560) pg/ml) (p<0.01). The plasma PEA concentrations in patients with Parkinson's disease treated with selegiline were prominently higher than in patients with no selegiline treatment (p<0.001). There was a significantly negative correlation between platelet MAO-B activity and plasma PEA concentrations in patients (n=24, r=-0.466, p<0.001). CONCLUSIONS: The increase in platelet MAO-B activity and decrease in plasma PEA concentrations in patients with Parkinson's disease may be involved in the pathophysiological processes of the disease, and these changes are reversed by treatment with selegiline.     

Monoamine oxidase B, smoking, and Parkinson's disease

Idiopathic Parkinson's disease (PD) has been reported to occur more commonly among non-smokers than among cigarette smokers, for reasons that are unknown. PD may possibly be caused by one or more unidentified neurotoxins which chemically resemble N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a substance which after conversion to an active neurotoxin by monoamine oxidase B (MAO-B) can extensively damage dopaminergic nigrostriatal neurons in humans, lower primates and mice. We measured MAO-B in autopsied brain of PD patients and control subjects and found enzyme activities similar. Inhibition of rat liver MAO-B by the urines of PD patients was greater than by urines of control subjects. These observations do not favour the hypothesis that idiopathic PD is due to excessive conversion of a precursor compound to an active neurotoxin by MAO-B. On the other hand, we found that MAO-B activity was significantly lower in the platelets of heavy cigarette smokers than in platelets of non-smokers. Finally, we found that hydrazine, a compound present in tobacco smoke, had a significant effect in mice in protecting dopaminergic nigrostriatal neurons from damage by MPTP. If idiopathic PD is caused by MPTP-like neurotoxins, accumulation of hydrazine in the tissues of cigarette smokers might explain their reduced likelihood of developing PD.     

Association of a monoamine oxidase B allele with Parkinson's disease

Monoamine oxidase B(MAO-B) is implicated in the cause of Parkinson's disease(PD) because of its role in metabolizing the neurotoxin 1-methyl–4-phenyl–1,2,3,6-tetrahydropyridine, and forming H₂O₂ during dopamine metabolism. Altered MAO-B activity has been observed in PD platelets. Polymerase chain reaction was used to amplify a portion of the MAO-B gene. Polymerase chain reaction products were screened with restriction enzymes to identify fragments useful for single-stranded conformational polymorphism analysis. A single-stranded conformational polymorphism was identified in an MAO-B polymerase chain reaction product after Hae III digestion. One hundred twenty-one control individuals were allelotyped with frequencies of 0.45 and 0.55 for alleles 1 and 2, respectively. Frequencies of 0.62 and 0.38 (1 and 2, respectively) were observed in a population of 46 patients with PD. The presence of MAO-B allele 1 is associated with a relative risk for PD of 2.03-fold (confidence interval, 1.44–2.61; p < 0.02). For comparison, a monoamine oxidase A polymorphism was used to determine allelic frequencies in these same populations and no statistically significant differences were found. These results suggest that an inherited variant of MAO-B may be involved in a genetic predisposition for PD.     

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.     

单胺氧化酶B基因多态与早发帕金森病的相关性

Objective To investigate the association between polymorphisms in monoamine oxidase B (MAO-B)and early-onset Parkinson's disease(EOPD).Methods Polymerase chsin reactionrestriction fragment length polymorphism was used to identify the genotypes of polymorphisms in MAO-B in 65 patients in EOPD group(early-onset age<50 years),60 in late-onset Parkinson's disease(LOPD) group(late-onset age≥160 years)and 66 healthy controls(<50 years).Results The frequency of AA genotype was higher in EOPD groups(49/65,75.4%)than in healthy controls(34/66,51.5%),and the difference between them was statistically significant(x2=8.075,P=0.018).The frequency of AA genotype between EOPD group and LOPD group,between LOPD group and healthy controls had no statistical significance.The frequency of AA genotype between male in EOPD group and male healthy controls,between female in EOPD group and female healthy controls had no statistical significance.The frequencies of AA genotype between male in EOPD group and LOPD group,between female in EOPD group and in LOPD group had no statistical significance.The frequency of AA genotype between male in LOPD group and in healthy controls,between female in LOPD group and female healthy controls had no statistical significance.The frequency of A alleles was higher in EOPD group(107/130,82.3%)than in healthy controls(87/132,65.9%)and the difierence between them was statistical significant(x2=9.165,P=0.002).The frequency of A allele between EOPD group and LOPD group,between LOPD group and healthy controls had no statistical significance. The frequency of A allele was higher in male EOPD group (60/70,85.7%) than in male healthy controls(51/72,70. 8% ), the difference between them was statistically significant (X2 =4. 606, P=0. 032) ;the frequency of A alleles was higher in female in EOPD group (47/60,78. 3% ) than in female healthy controls(36/60,60. 0% ), the difference between them was statistical significance( x2 =4. 728, P = 0. 030). The frequency of A alleles between male EOPD group and male LOPD group, between female EOPD group and female LOPD group had no statistical significance. The frequency of A allele between male LOPD group and male healthy controls, between female LOPD group and female healthy controls had no statistical significance. Conclusions The AA genotype of MAO-B is the risk factor of EOPD. The A allele of MAO-B is a risk factor of EOPD group for both male and female.     

单胺氧化酶B基因多态与早发帕金森病的相关性

Objective To investigate the association between polymorphisms in monoamine oxidase B (MAO-B)and early-onset Parkinson's disease(EOPD).Methods Polymerase chsin reactionrestriction fragment length polymorphism was used to identify the genotypes of polymorphisms in MAO-B in 65 patients in EOPD group(early-onset age<50 years),60 in late-onset Parkinson's disease(LOPD) group(late-onset age≥160 years)and 66 healthy controls(<50 years).Results The frequency of AA genotype was higher in EOPD groups(49/65,75.4%)than in healthy controls(34/66,51.5%),and the difference between them was statistically significant(x2=8.075,P=0.018).The frequency of AA genotype between EOPD group and LOPD group,between LOPD group and healthy controls had no statistical significance.The frequency of AA genotype between male in EOPD group and male healthy controls,between female in EOPD group and female healthy controls had no statistical significance.The frequencies of AA genotype between male in EOPD group and LOPD group,between female in EOPD group and in LOPD group had no statistical significance.The frequency of AA genotype between male in LOPD group and in healthy controls,between female in LOPD group and female healthy controls had no statistical significance.The frequency of A alleles was higher in EOPD group(107/130,82.3%)than in healthy controls(87/132,65.9%)and the difierence between them was statistical significant(x2=9.165,P=0.002).The frequency of A allele between EOPD group and LOPD group,between LOPD group and healthy controls had no statistical significance. The frequency of A allele was higher in male EOPD group (60/70,85.7%) than in male healthy controls(51/72,70. 8% ), the difference between them was statistically significant (X2 =4. 606, P=0. 032) ;the frequency of A alleles was higher in female in EOPD group (47/60,78. 3% ) than in female healthy controls(36/60,60. 0% ), the difference between them was statistical significance( x2 =4. 728, P = 0. 030). The frequency of A alleles between male EOPD group and male LOPD group, between female EOPD group and female LOPD group had no statistical significance. The frequency of A allele between male LOPD group and male healthy controls, between female LOPD group and female healthy controls had no statistical significance. Conclusions The AA genotype of MAO-B is the risk factor of EOPD. The A allele of MAO-B is a risk factor of EOPD group for both male and female.     

单胺氧化酶B基因多态与早发帕金森病的相关性

目的 探讨单胺氧化酶B(MAO-B)基因型和等位基因与早发帕金森病(early-onset Parkinson's disease,EOPD)的关系.方法 采取聚合酶链反应-限制性片段长度多态性(PCR-RFLP)的方法,研究65例EOPD患者(<50岁)、60例晚发PD(late-onset Parkinson's disease,LOPD)患者(≥60岁)和66名健康对照者(<50岁)的基因型频率和等位基因频率的分布差异.结果 EOPD组的AA基因型频率(49/65,75.4%)高于健康对照组(34/66,51.5%),差异有统计学意义(x2=8.075,P=0.018);LOPD组分别与EOPD组、健康对照组的从基因型频率比较,差异无统计学意义;男性EOPD组分别与男性健康对照组、男性LOPD组,女性EOPD组分别与女性健康对照组、女性LOPD组的AA基因型频率比较,差异无统计学意义;男性LOPD组与男性健康对照组、女性LOPD组与女性健康对照组的AA基因型频率比较,差异无统计学意义.EOPD组的A等位基因频率(107/130,82.3%)高于健康对照组(87/132,65.9%),差异有统计学意义(X2=9.165,P=0.002);LOPD组分别与EOPD组、健康对照组的A等位基因频率比较,差异无统计学意义;男性EOPD组的A等位基因频率(60/70,85.7%)高于男性健康对照组(51/72,70.8%),差异有统计学意义(x2=4.606,P=0.032);女性EOPD组的A等位基因频率(47/60,78.3%)高于女性健康对照组(36/60,60.0%),差异有统计学意义(x2=4.728,P=0.030);男性LOPD组分别与男性EOPD组、男性健康对照组,女性LOPD组分别与女性EOPD组、女性健康对照组的A等位基因频率比较,差异均无统计学意义.结论 MAO-B的从基因型频率增高是EOPD组发病的危险因素;MAO-B的A等位基因频率增高是EOPD组、男性EOPD组及女性EOPD组发病的危险因素.     

Peripheral blood cell activities of monoamine oxidase B and superoxide dismutase in Parkinson's disease

Summary Monoamine oxidase type B (MAO-B) and superoxide dismutase (SOD) are two enzyme stystems that are potentially relevant to an oxidative stress model of Parkinson's disease (PD) causation. Activities of MAO-B in platelets (nmol/10⁸ cells/hr) and total SOD in lymphocytes (U/mg protein) were assayed among 28 cases of idiopathic PD and 22 controls. As anticipated, MAO-B was lowest in PD cases on selegiline (L-deprenyl) therapy (mean 1.10). There was a slight deficit of MAO-B among male cases not taking selegiline compared to controls (3.78 vs. 4.15), but the opposite trend was observed for females (6.18 vs. 4.16). SOD was slightly higher in cases (7.40), than controls (6.81). Excess SOD among PD cases was seen irrespective of gender, age, or selegiline treatment, although none of the differences was statistically significant Future research on SOD should take advantage of the availability of assays specific for the cytosolic and mitochondrial forms of the enzyme.     

Variations in the monoamine oxidase B (MAOB) gene are associated with Parkinson's disease.

The monoamine oxidase B gene (MAOB; Xp15.21-4) is a candidate gene for Parkinson's disease (PD) given its role in dopamine metabolism and its possible role in the activation of neurotoxins. The association of MAOB polymorphisms (a [GT] repeat allelic variation in intron 2 and an A-G transition in intron 13) with Parkinson's disease (PD) was studied in an Australian cohort of 204 (male:female ratio 1.60) people with PD and 285 (male:female ratio 1.64) age- and gender-matched control subjects. Genomic DNA was extracted from venous blood and polymerase chain reaction was used to amplify the appropriate regions of the MAOB gene. The length of each (GT) repeat sequence was determined by 5% polyacrylamide denaturing gel electrophoresis and a DNA fragment analyzer, while the G-A genotype was determined using 2% agarose gel electrophoresis. The G-A polymorphism showed no association with PD (odds ratio [OR] = 0.80; p = 0.51; 95% confidence interval [CI] = 0.42-1.53). There was a significant difference in allele frequencies of the (GT) repeat allelic variation between patients and control subjects (chi2 = 20.09; p<0.01). After statistical adjustment for potential confounders using a logistic regression analysis, the (GT) repeat alleles > or =188 base pairs in the intron 2 marker of the MAOB gene were significantly associated with PD (OR = 4.60; p<0.00005; 95% CI = 1.97-10.77). The 186 base pair allele was also significantly associated with PD (OR = 1.85; p = 0.048; 95% CI = 1.01-3.42). The GT repeat in intron 2 of the MAOB gene is a powerful marker for PD in this large Australian cohort.     

Catechol-O-methyltransferase and monoamine oxidase B genes and susceptibility to sporadic Parkinson's disease in a Polish population

Recent reports have proved that genetic factors play a role in the pathogenesis of sporadic Parkinson's disease (PD). It has been suggested that polymorphisms in monoamine oxidase B (MAOB) and catechol-O-methyltransferase (COMT) might increase the risk of PD. A total of 210 Polish patients with sporadic PD and 152 healthy controls were studied. The MAOB and COMT polymorphisms were identified using the polymerase chain reaction-restriction fragment length polymorphism method. The MAOB allele and genotype frequencies in PD patients did not differ significantly from the controls. A statistically lower frequency of the COMTLL genotype in patients with parkinsonism was found. The combined haplotype of the MAOB G (G/G) and COMTHL genotype showed a fourfold increase (p < 0.05) in the risk of PD in female patients in this Polish population.     

Genetic polymorphism of dopamine D2 receptors in Parkinson's disease and interactions with cigarette smoking and MAO-B intron 13 polymorphism

Genetic polymorphisms of dopamine D2 receptors (DRD2) may be susceptibility factors for Parkinson's disease due to their influence on dopamine response and association with cigarette smoking, which is inversely related to risk of Parkinson's disease. Relations of TaqIA and TaqIB DRD2 genotypes with Parkinson's disease were investigated and tested for interactive effects with smoking and the monoamine oxidase B (MAO-B) intron 13 polymorphism previously found to be related to smoking. Study subjects were 152 cases of idiopathic Parkinson's disease and 231 controls. The smoking history of all genotyped subjects was known. Subjects of genotype B12 were more frequent among cases than controls (27% and 23.8%, respectively), and were more frequent among "ever smokers" than "never smokers", among controls (27.8% and 17.2%, respectively), although these associations were not statistically significant. Neither TaqIA or TaqIB genotypes modified the inverse relation of smoking and Parkinson's disease. When genotypes for DRD2 were considered in combination with genotypes for intron 13 of MAO-B, genotype combinations with high risk of Parkinson's disease were found; although the MAO-B/DRD2 interaction did not reach statistical significance after Bonferroni correction for multiple comparisons, these results are suggestive of a possible synergism between MAOB and DRD2 genes with respect to Parkinson's disease.     

Recent advances in Parkinson's disease therapy: use of monoamine oxidase inhibitors

Monoamine oxidase inhibitors inhibit dopamine metabolism and are therefore effective in treating Parkinson's disease, a condition associated with progressive striatal dopamine deficiency secondary to degeneration of dopaminergic neurons in the substantia nigra. Selegiline is currently the most widely used monoamine oxidase-B inhibitor for Parkinson's disease, but has a low and variable bioavailability, and is metabolized to L-methamphetamine and L-amphetamine that carry a risk for potential neurotoxicity. There are two new approaches that circumvent these potential disadvantages. First, selegiline orally disintegrating tablets provide a novel delivery form of selegiline, avoiding first pass metabolism by rapid absorption through the oral mucosa, thus leading to significantly lower plasma concentrations of L-metamphetamine and L-amphetamine. Selegiline orally disintegrating tablets prove to be clinically effective and safe in patients with moderately advanced Parkinson's disease. Second, rasagiline is a new monoamine oxidase inhibitor, without known neurotoxic metabolites. In large clinical trials, rasagiline proves effective as monotherapy in early Parkinson's disease, as well as adjunctive therapy to levodopa in advanced disease. Clinical data suggest, in addition, a disease-modifying effect of rasagiline that may correlate with neuroprotective activity of monoamine oxidase-B inhibitors in animal models of Parkinson's disease.     

Endogenous urinary monoamine oxidase inhibitor excretion in Parkinson's disease and other neurological disorders

Summary In this study, urinary output of both neutral (tribulin) and basic monoamine oxidase inhibitory activity was measured in parkinsonian patients, other neurological patients and controls. No significant differences in output were found between these different groups. In general, tribulin output rose with age, in parallel with known changes in monoamine oxidase B activity.     

An allelic association study of monoamine oxidase B in parkinson's disease

A single-stranded conformational polymorphism in the monoamine oxidase B gene was shown to be A or G, 36 bases upstream from the intron 13-exon 14 boundary. An allelic association study revealed no statistically significant associations between this single-base polymorphism and Parkinson's disease, unlike the results of a previous study.     

Molecular mechanism of the relation of monoamine oxidase B and its inhibitors to Parkinson's disease: possible implications of glial cells

Monoamine oxidases A and B (MAO A and MAO B) are the major enzymes that catalyze the oxidative deamination of monoamine neurotaransmitters such as dopamine (DA), noradrenaline, and serotonin in the central and peripheral nervous systems. MAO B is mainly localized in glial cells. MAO B also oxidizes the xenobiotic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to a parkinsonism-producing neurotoxin, 1-methyl-4-phenyl-pyridinium (MPP+). MAO B may be closely related to the pathogenesis of Parkinson's disease (PD), in which neuromelanin-containing DA neurons in the substantia nigra projecting to the striatum in the brain selectively degenerate. MAO B degrades the neurotransmitter DA that is deficient in the nigro-striatal region in PD, and forms H2O2 and toxic aldehyde metabolites of DA. H2O2 produces highly toxic reactive oxygen species (ROS) by Fenton reaction that is catalyzed by iron and neuromelanin. MAO B inhibitors such as L-(-)-deprenyl (selegiline) and rasagiline are effective for the treatment of PD. Concerning the mechanism of the clinical efficacy of MAO B inhibitors in PD, the inhibition of DA degradation (a symptomatic effect) and also the prevention of the formation of neurotoxic DA metabolites, i.e., ROS and dopamine derived aldehydes have been speculated. As another mechanism of clinical efficacy, MAO B inhibitors such as selegiline are speculated to have neuroprotective effects to prevent progress of PD. The possible mechanism of neuroprotection of MAO B inhibitors may be related not only to MAO B inhibition but also to induction and activation of multiple factors for anti-oxidative stress and anti-apoptosis: i.e., catalase, superoxide dismutase 1 and 2, thioredoxin, Bcl-2, the cellular poly(ADP-ribosyl)ation, and binding to glyceraldehydes-3-phosphate dehydrogenase (GAPDH). Furthermore, it should be noted that selegiline increases production of neurotrophins such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial cell line-derived neurotrphic factor (GDNF), possibly from glial cells, to protect neurons from inflammatory process.