Parkinson's disease: the first common neurological disease due to auto-intoxication?
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.
Williams
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Division of Neurosciences, University of Birmingham, Edgbaston, Birmingham. D.B.Ramsden@bham.ac.uk
Cartwright
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LS
Ramsden
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D001921:Brain / Q000378:metabolism; D004777:Environment; D020022:Genetic Predisposition to Disease; D006801:Humans; D008658:Inactivation, Metabolic; D008780:Methyltransferases / Q000502:physiology; D009536:Niacinamide / Q000378:metabolism; D050903:Nicotinamide N-Methyltransferase; D010300:Parkinson Disease / Q000209:etiology* / Q000378:metabolism; D012307:Risk Factors; D015262:Xenobiotics / Q000633:toxicity*
D015262:Xenobiotics; D009536:Niacinamide; D008780:Methyltransferases; C494406:NNMT protein, human; D050903:Nicotinamide N-Methyltransferase