STUDIES ON THE PATHOGENESIS OF PARKINSONS-DISEASE IN JAPAN

Studies on the pathogenesis of nigral cell death in Parkinson's diseas e (PD) are reviewed. Discussions are focused mainly on studies perform ed by Japanese investigators because of the purpose of this issue. We and other groups found a decrease in complex I of the mitochondrial el ectron transfer complex in the substantia nigra of patients with PD, a nd in addition to complex I deficiency, we reported loss of alpha-keto glutarate dehydrogenase complex of the tricarboxylic acid cycle (TCA c ycle) by immunohistochemistry. Thus mitochondrial respiratory failure and resultant energy crisis appear to be one of the most important mec hanisms that lead nigral neurons to cell death. The primary cause of m itochondrial respiratory failure has not been elucidated yet; however, environmental neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydr opyridine (MPTP) may be responsible for nigral cell death in PD; in th is respect a number of candidate toxins including tetrahydroisoquinoli nes and beta-carbolines have extensively been studied for nigral as we ll as mitochondrial toxicity. Recent progress in this field is also re viewed. Even if an environmental neurotoxin is involved in PD, exposur e to such a neurotoxin alone may not account for its pathogenesis, as most of us are probably being exposed to the same toxin. Therefore, ge netic predisposition appears to be essential for the development of PD . The genetic predisposition may involve hepatic detoxifying enzymes f or such neurotoxins, the transport mechanism of those toxins to the br ain, bioactivation of those toxins in the brain, the uptake mechanism to the nigral neurons, and the activity levels of target enzymes or pr oteins; all of these factors are being extensively studied in many lab oratories at a molecular level.