Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Parkinson's disease (PD) may be initiated or precipitated by endogenous toxins with a structure similar to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in genetically-predisposed individuals. Nicotinamide N-methyltransferase (NNMT) catalyzes N-methylation of nicotinamide and other pyridines to form pyridinium ions. The protein amount of NNMT was measured in the lumbar cerebrospinal fluid of PD patients by immunoblot analysis using anti-human NNMT antibody. In younger (65 years old or younger) PD patients, the relative level of NNMT protein was significantly higher than that in younger controls. The NNMT protein was significantly affected by aging: the amount decreased along with aging in PD patients. These findings suggested that excess NNMT in the central nervous system might be implicated in the PD pathogenesis.
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PMID:Nicotinamide-N-methyltransferase is higher in the lumbar cerebrospinal fluid of patients with Parkinson's disease. 1115 40

Nicotinamide N-methyltransferase (NNMT) has been proposed as a link between the environmental and genetic factors of Parkinson disease (PD). Therefore, we explored the hypothesis that high levels of NNMT expression may predispose to the development of PD. Regions of high mRNA expression were shown in the spinal cord, medulla, and temporal lobe, with lowest expression in the cerebellum, subthalamic nucleus, and caudate nucleus. Using 2 NNMT antibodies, the protein was shown to be expressed in multipolar neurons in the temporal lobe, caudate nucleus, and spinal cord, granular neurons of the cerebellum, dopaminergic neurons in the substantia nigra, and in the axons of the third nerve. Expression of NNMT was compared in PD and non-PD control cerebella and caudate nucleus. PD tissue exhibited significantly increased levels of NNMT protein and activity. PD disease duration was inversely correlated with the level of expression in cerebellum. This is the first demonstration that patients with PD have higher levels of NNMT activity and protein in brain tissue than those without PD and that NNMT expression is associated with neurons that degenerate in PD.
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PMID:Expression of nicotinamide N-methyltransferase (E.C. 2.1.1.1) in the Parkinsonian brain. 1185 16

This study tested the hypothesis, that nicotinamide N-methyltransferase (NAMT) activity in the brain could convert nicotinamide to 1-methylnicotinamide (MNA) and by that means damage the nigro-neostriatal dopaminergic neurons. The NAMT activities of rat brain and liver were assayed with gas chromatographic-mass spectrometric analysis in a selected ion monitoring system. They amounted to 0.30 nmol/mg x h and 0.51 nmol/mg x h, respectively. The MNA injection in rat substantia nigra pars compacta significantly decreased dopamine content in the striatum. NADH oxidation and lipid peroxidation by MNA via rat brain submitochondrial particles (SMP) under the condition of pH ranging from pH 6.0 to 10.0 were verified. The pH optimum for the NADH oxidation was 9.0. The pH optimum for the peroxidation of the lipid composing SMP by MNA was also 9.0. The lipid peroxidation in this assay was suppressed by superoxide dismutase. The superoxide anion formed by MNA via mitochondria might be involved in the etiology of Parkinson's disease.
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PMID:Possible role of 1-methylnicotinamide in the pathogenesis of Parkinson's disease. 1192 89

The discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) leads to the hypothesis that Parkinson's disease (PD) is maybe initiated or precipitated by environmental or endogenous toxins by the mechanism similar to that of MPTP in genetically-predisposed individuals. Endogenous analogs of MPTP, such as beta-carbolines (betaCs) and tetrahydroisoquinolines, have been proposed as possible causative candidates causing PD and are bioactivated into potential neurotoxins by N-methylation enzyme(s). These N-methylated betaCs and tetrahydroisoquinoline have been higher cerebrospinal levels in parkinsonian patients than age-matched controls. Thus, there is a hypotheses to influence the pathogenesis of PD, that is, the excess enzyme activity to activate neurotoxins, such as N-methyltransferase, might be higher in PDs. Indeed, simple betaCs, via N-methylation steps, induced bradykinesia with the decreased dopamine contents in the striatum and midbrain in C57/BL mice. In younger (65 years old) PD patients, the excretion amount of N(1)-methyl-nicotinamaide was significantly higher than that in younger controls. The protein amount of nicotinamide N-methyltransferase (NNMT) was also significantly higher in younger PD patients than that in younger controls. These findings described here would indicate that the excess N-methylation ability for azaheterocyclic amines, such as betaCs, before the onset had been implicated in PD pathogenesis. On the other hand, the contribution of aberrant cytochrome P450 or aldehyde oxidase activity acting on the pyridine ring, that could act as detoxification routes of endogenous neurotoxins, would be small in the etiology of PD.
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PMID:N-methylation underlying Parkinson's disease. 1220 Jan 90

We have previously speculated that elevated levels of nicotinamide N-methyltransferase (NNMT), the primary catabolic enzyme of nicotinamide, may result in reduced Complex I activity in idiopathic Parkinson's disease (IPD) in two ways: (1) reduction in the levels of nicotinamide available for nicotinamide adenine dinucleotide synthesis; and (2) increased methylation of compounds such as tetrahydroisoquinolines and beta-carbolines, which are potent Complex I inhibitors. Expression of NNMT was assessed in 91 cerebella (53 IPD, 38 control) using immunohistochemistry coupled with quantitative digital image analysis. Control cerebella showed a distribution of expression ascribed to low, intermediate and high expressors with ratios of 1:2:1 categories. Expression in the parkinsonian cerebella was significantly higher than in the control group (control group median expression 17%, mean expression 16.6%, range 0-51%, standard deviation 11.4%, standard error 1.9%; IPD group median expression 46%, mean expression 53.7%, range 21-100%, standard deviation 23.4%, standard error 3.2%; P<0.0001; unpaired t-test with Welch correction (parametric) and Mann-Whitney U-test (non-parametric)). These results confirm that NNMT expression is elevated in IPD, which may ultimately lead to neurodegeneration via a reduction in Complex I activity.
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PMID:High expression of nicotinamide N-methyltransferase in patients with idiopathic Parkinson's disease. 1272 6

Xenobiotic enzymes normally protect against toxins but on occasion can convert protoxins into toxins. N-methylated pyridines (such as the N-methyl-4 phenylpyridinium ion (MPP+)) are well-established dopaminergic toxins. The enzyme nicotinamide N-methyltransferase (NNMT) can covert otherwise harmless pyridines such as 4-phenylpyridine into MPP+ like compounds. This enzyme has recently been shown to be present in the human brain, which is a necessity for neurotoxicity, as charged compounds such as MPP+ cannot cross the blood brain barrier. Moreover, it is present in increased concentration in the brain of patients with Parkinson's disease (PD). This would increase MPP+ like compounds at the same time as decreasing intraneuronal nicotinamide, a neuroprotectant at several levels, thus creating a "multiple hit", as additionally complex 1 of the mitochondrial complex would also be poisoned and starved of its major substrate, nicotinamide adenine dinucleotide (NAD). Thus, PD may be a disease of autointoxication. Xenobiotic enzyme inhibitors of NNMT, with or without dietary modification, would be a novel way to attempt primary prevention of PD.
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PMID:Autotoxicity, methylation and a road to the prevention of Parkinson's disease. 1563 3

Parkinson's disease may be a disease of autointoxication. N-methylated pyridines (e.g. MPP+) are well-established dopaminergic toxins, and the xenobiotic enzyme nicotinamide N-methyltransferase (NNMT) can convert pyridines such as 4-phenylpyridine into MPP+, using S-adenosyl methionine (SAM) as the methyl donor. NNMT has recently been shown to be present in the human brain, a necessity for neurotoxicity, because charged compounds cannot cross the blood-brain barrier. Moreover, it is present in increased concentration in parkinsonian brain. This increase may be part genetic predisposition, and part induction, by excessive exposure to its substrates (particularly nicotinamide) or stress. Elevated enzymic activity would increase MPP+-like compounds such as N-methyl nicotinamide at the same time as decreasing intraneuronal nicotinamide, a neuroprotectant at several levels, creating multiple hits, because Complex 1 would be poisoned and be starved of its major substrate NADH. Developing xenobiotic enzyme inhibitors of NNMT for individuals, or dietary modification for the whole population, could be an important change in thinking on primary and secondary prevention.
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PMID:Parkinson's disease: the first common neurological disease due to auto-intoxication? 1572 3

Monkeys and man are very closely related genetically. Yet intellectually there are big differences and they suffer from a broad range of different diseases. For example, monkeys do not get Parkinson's or Alzheimer's disease. The former is surprising given that both get parkinsonism from MPTP poisoning and the latter initially less surprising as the cortex predominantly affected in Alzheimer's never developed as fully in the monkey. Man is an omnivore whilst other primates are predominantly herbivores. The one primate who was almost wholly carnivorous was Neanderthal man who became extinct. Red meat has a high content of Nicotinamide, Choline, and methyl donors. The enzyme NNMT converts nicotinamide to N-methyl-nicotinamide using SAM as the methyl donor. It is not present to any degree in herbivores. It has recently been shown to be present in human brain and up regulated in Parkinson's disease. Omnivores presumably need it for nicotinamide homeostasis but the production of N-methyl-nicotinamide will also be beneficial as it will reduce the export of Choline from neurones. Both will aid brain growth and development. However, as N-methyl-nicotinamide resembles MPTP it could cause parkinsonism later in life for man but not monkeys as they would be predicted not to have as much NNMT. Humans with a diet low in Nicotinamide,Choline or methyl donors early in life and low enzyme activity may be prone to Alzheimer's as their brain and therefore its reserves may never have developed as fully. The possession of NNMT plus a diet rich in Nicotinamide, Choline and methyl providers may explain many of the advantages but also the disadvantages of the human condition. One prediction is that a diet rich in these micronutrients whilst young will improve brain development and reduce the risk of Alzheimer's but that a lower dose later in life will reduce the risk of Parkinsonism. A second prediction is that it will become clear that dietary factors including vitamins are signalers and at the head of vital biochemical pathways. A time point will be reached when errors emerge that could not be deleted by evolutionary pressures. Finding and rectifying them will be the key to preventing many common diseases.
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PMID:Nicotinamide homeostasis: a xenobiotic pathway that is key to development and degenerative diseases. 1592 12

NNMT (nicotinamide N-methyltransferase, E.C. 2.1.1.1) catalyses the N-methylation of nicotinamide to 1-methylnicotinamide. NNMT expression is significantly elevated in a number of cancers, and we have previously demonstrated that NNMT expression is significantly increased in the brains of patients who have died of Parkinson's disease. To investigate the cellular effects of NNMT overexpression, we overexpressed NNMT in the SH-SY5Y cell line, a tumour-derived human dopaminergic neuroblastoma cell line with no endogenous expression of NNMT. NNMT expression significantly decreased SH-SY5Y cell death, which correlated with increased intracellular ATP content, ATP/ADP ratio and Complex I activity, and a reduction in the degradation of the NDUFS3 [NADH dehydrogenase (ubiquinone) iron-sulfur protein 3] subunit of Complex I. These effects were replicated by incubation of SH-SY5Y cells with 1-methylnicotinamide, suggesting that 1-methylnicotinamide mediates the cellular effects of NNMT. Both NNMT expression and 1-methylnicotinamide protected SH-SY5Y cells from the toxicity of the Complex I inhibitors MPP+ (1-methyl-4-phenylpyridinium ion) and rotenone by reversing their effects upon ATP synthesis, the ATP/ADP ratio, Complex I activity and the NDUFS3 subunit. The results of the present study raise the possibility that the increase in NNMT expression that we observed in vivo may be a stress response of the cell to the underlying pathogenic process. Furthermore, the results of the present study also raise the possibility of using inhibitors of NNMT for the treatment of cancer.
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PMID:The expression of nicotinamide N-methyltransferase increases ATP synthesis and protects SH-SY5Y neuroblastoma cells against the toxicity of Complex I inhibitors. 2135 99

Epidemiological surveys suggest an important role for niacin in the causes of Parkinson's disease, in that niacin deficiency, the nutritional condition that causes pellagra, appears to protect against Parkinson's disease. Absorbed niacin is used in the synthesis of nicotinamide adenine dinucleotide (NAD) in the body, and in the metabolic process NAD releases nicotinamide by poly(ADP-ribosyl)ation, the activation of which has been reported to mediate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's disease. Recently nicotinamide N-methyltransferase (EC2.1.1.1) activity has been discovered in the human brain, and the released nicotinamide may be methylated to 1-methylnicotinamide (MNA), via this enzyme, in the brain. A deficiency in mitochondrial NADH: ubiquinone oxidoreductase (complex 1) activity is believed to be a critical factor in the development of Parkinson's disease. MNA has been found to destroy several subunits of cerebral complex 1, leading to the suggestion that MNA is concerned in the pathogenesis of Parkinson's disease. Based on these findings, it is hypothesized that niacin is a causal substance in the development of Parkinson's disease through the following processes: NAD produced from niacin releases nicotinamide via poly(ADP-ribosyl)ation, activated by the hydroxyl radical. Released excess nicotinamide is methylated to MNA in the cytoplasm, and superoxides formed by MNA via complex I destroy complex 1 subunits directly, or indirectly via mitochondrial DNA damage. Hereditary or environmental factors may cause acceleration of this cycle, resulting in neuronal death.
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PMID:Niacin metabolism and Parkinson's disease. 2143 57


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