Toxic effects of dopamine metabolism in Parkinson's disease.
Levodopa is the most effective medication for Parkinson's disease (PD). In contrast, there is evidence that levodopa and its metabolites such as dopa/dopamine quinone are toxic for nigral neurons based on in vitro studies. Moreover, there is growing evidence that oxidative stress and mitochondrial dysfunction contribute the pathogenesis of PD. Thus, studies for oxidative stress give us good information for elucidating the pathogenesis of PD. In this regard, it is mandatory to develop markers such as 4-hydroxy-nonenal (HNE). HNE is a product of lipid peroxidation. Indeed, immunohistochemical studies have revealed that HNE-modified proteins accumulate within ragged red fibers (RRFs). This finding indicated that mitochondrial impairment may be linked to oxidative stress. Moreover, HNE-modified proteins accumulate in nigral neurons. In PD, mitochondrial dysfunction such as complex I deficiency has also been reported. In addition, HNE can modify alpha-synuclein (SNCA). Subsequently, this modification may trigger the aggregation of this protein. At a minimum, this modification could be associated with oligomer formation or fibrillation of SNCA.
Hattoria
Nobutaka
N
Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo, Tokyo 113-8421, Japan. nhattori@med.juntendo.ac.jp
Wanga
Mei
M
Taka
Hikari
H
Fujimura
Tsutomu
T
Yoritaka
Asako
A
Kubo
Shin-Ichiro
S
Mochizuki
Hideki
H
D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D004298:Dopamine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000633:toxicity; D006801:Humans; D007980:Levodopa / Q000378:metabolism / Q000627:therapeutic use; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology; D010300:Parkinson Disease / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism
D000447:Aldehydes; D051844:alpha-Synuclein; C462359:tert-4-hydroxy-2-nonenal; D007980:Levodopa; C104705:dopamine quinone; D004298:Dopamine