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Elevation of heme oxygenase‐1 by proteasome inhibition affords dopaminergic neuroprotection
Author(s) -
Yamamoto Noriyuki,
Izumi Yasuhiko,
Matsuo Takaaki,
Wakita Seiko,
Kume Toshiaki,
TakadaTakatori Yuki,
Sawada Hideyuki,
Akaike Akinori
Publication year - 2010
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.22363
Subject(s) - lactacystin , heme oxygenase , mg132 , proteasome , neuroprotection , proteasome inhibitor , cycloheximide , downregulation and upregulation , protein degradation , zinc protoporphyrin , chemistry , pharmacology , heme , biology , biochemistry , protein biosynthesis , gene , enzyme
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. © 2010 Wiley‐Liss, Inc.