[Pathogenesis of idiopathic Parkinson's disease]

The pathogenesis of idiopathic Parkinson's disease (PD) remains to be elucidated. The discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) suggests that neurotoxins in the human brain may cause selective depletion of striatal dopamine neurons, a hallmark of PD. An endogenous isoquinoline, N-methyl(R)salsolinol is a most promising neurotoxin candidate, and it was proved to be selectively toxic to dopamine neurons in the rat brain by in vivo experiments. The level of N-methyl(R)salsolinol in the cerebrospinal fluid obtained from PD patients was significantly higher than control. N-Methyl(R)salsolinol is synthesized by 2 enzymatic reactions from dopamine; condensation of dopamine with acetaldehyde into (R)salsolinol by (R)salsolinol synthase and N-methylation of (R)salsolinol by neutral(R)salsolinol N-methyltransferase. The second enzyme, which catabolizes the N-methylation of (R)salsolinol, was found to determine the level of the neurotoxin in the brain. The activity of neutral(R)salsolinol N-methyltransferase was examined using lymphocytes prepared from PD patients, normal controls and diseased controls as enzyme source. A significant increase in the activity was confirmed in lymphocytes from PD cases compared to normal- and diseased-control. Studies to clarify the environmental and genetic factors determining the activity of the enzyme are now under the way. The cytotoxicity of N-methyl(R)salsolinol was examined using a cultured cell model. N-Methyl(R)salsolinol was found to induce apoptotic cell death in a dose-dependent way. The mechanism of apoptosis was clarified to be mediated by collapse in mitochondrial membrane potential, activation of caspase 3 and fragmentation of nuclear DNA. In addition, propargylamines protected the cells from apoptosis. It was suggested that N-methyl(R)salsolinol and propargylamines have specific binding sites in mitochondria which regulate the death signal transduction. Propargylamines might be applicable as neuroprotective drugs, which can be orally administrated to PD patients.