[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.
Maruyama
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D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000378:metabolism*; D006801:Humans; D008780:Methyltransferases / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D010300:Parkinson Disease / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D012490:Salsoline Alkaloids / Q000134:cerebrospinal fluid / Q000378:metabolism*; D044005:Tetrahydroisoquinolines
D018696:Neuroprotective Agents; D012490:Salsoline Alkaloids; D044005:Tetrahydroisoquinolines; C032837:salsoline; D008780:Methyltransferases; C118573:salsolinol N-methyltransferase