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.