Autotoxicity, methylation and a road to the prevention of Parkinson's disease

Abstract

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.