Elevation of heme oxygenase-1 by proteasome inhibition affords dopaminergic neuroprotection.
Postmortem studies have shown that heme oxygenase-1 (HO-1) immunoreactivity is increased in patients with Parkinson disease. HO-1 expression is highly upregulated by a variety of stress. Since the proteasome activity is decreased in patients with Parkinson disease, we investigated whether proteasome activity regulates HO-1 content. MG-132, a proteasome inhibitor, increased the amount of HO-1 protein mainly in astrocytes of primary mesencephalic cultures. Quantitative RT-PCR analysis revealed that lactacystin upregulated HO-1 mRNA expression. Proteasome inhibition with MG132 also increased the cytomegalovirus promoter-driven expression of Flag-HO-1 protein and resulted in an accumulation of ubiquitinated Flag-HO-1 in Flag-HO-1-overexpressing PC12 cells. In addition, a cycloheximide chase assay demonstrated that the degradation of Flag-HO-1 protein was slowed by MG-132. Next, the function of HO-1 which was upregulated by proteasome inhibitors was examined. Proteasome inhibitors protected dopaminergic neurons from 6-hydroxydopamine (6-OHDA)-induced toxicity and this neuroprotection was abrogated by co-treatment with zinc protoporphyrin IX, a HO-1 inhibitor. Furthermore, 6-OHDA-induced toxicity was blocked by bilirubin and carbon monoxide, products of the HO-1-catalyzed degradation of heme. These results suggest that mesencephalic HO-1 protein level is regulated by proteasome activity and the elevation by proteasome inhibition affords neuroprotection.
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
Noriyuki
N
Yamamoto
Yasuhiko
Y
Izumi
Takaaki
T
Matsuo
Seiko
S
Wakita
Toshiaki
T
Kume
Yuki
Y
Takada-Takatori
Hideyuki
H
Sawada
Akinori
A
Akaike
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism*; D004795:Enzyme Stability / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D008636:Mesencephalon / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D016716:PC12 Cells; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D054875:Ubiquitination
D061988:Proteasome Inhibitors; D012333:RNA, Messenger; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C491523:Hmox1 protein, rat; D046988:Proteasome Endopeptidase Complex; D004298:Dopamine