Studies on endogenous toxins as pathogenic factors in idiopathic Parkinson's disease

Abstract

The etiology of idiopathic Parkinson's disease remains as an enigma. N-Methyl (R) salsolinol [NM(R)Sal] is a candidate of dopaminergic neurotoxins, and is synthesized from dopamine by 2 enzymes: (R) Salsolinol synthase and a neutral (R) Salsolinol N-methyltransferase (nNMT). NM(R)Sal injection in the rat striatum caused selective depletion of dopamine neurons in the substantia nigra without tissue reaction, suggesting NM(R)Sal induced apoptosis in dopamine neurons. NM(R)Sal level was found to increase significantly in the cerebrospinal fluid of parkinsonian patients, and NM(R)Sal accumulated in the nigrostriatum. By the analysis of the human brain, it was suggested nNMT is the rate-limiting step to synthesize dopamine-derived neurotoxins. The activity of nNMT was found to increase in the lymphocytes from parkinsonian patients. The mechanism of toxicity by NM(R)Sal was studied in vitro using human dopaminergic neuroblastoma SH-SY5Y cells. NM(R)Sal induced apoptosis stereo-specifically, suggesting that a molecule in mitochondria can distinguish the stereo-chemical structure of NM(R)Sal and activate intracellular signal of apoptosis. Recently, we found that propargylamines, inhibitors of type B monoamine oxidase, can prevent the apoptosis induced by NM(R)Sal. Further study on the mechanism underlying increase in nNMT activity in parkinsonian patients will clarify the involvement of genetic and environmental factors in the pathogenesis of Parkinson's disease.