Autotoxicity, methylation and a road to the prevention of Parkinson's disease.
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.
Williams
Adrian C
AC
Centre for Neuroscience, Queen Elizabeth Hospital, and Department of Medicine, University of Birmingham, Edgbaston, Birmingham, B15 2TH, UK. Andrea.McCaery@uhb.nhs.uk
Ramsden
David B
DB
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D015259:Dopamine Agents; D006801:Humans; D008745:Methylation; D009536:Niacinamide / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced; D012307:Risk Factors; D012436:S-Adenosylmethionine / Q000378:metabolism
D015259:Dopamine Agents; D009536:Niacinamide; D012436:S-Adenosylmethionine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine