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Title: Compensatory role of the Nrf2-ARE pathway against paraquat toxicity: Relevance of 26S proteasome activity
Authors: Izumi, Yasuhiko
Yamamoto, Noriyuki
Matsushima, Sayaka
Yamamoto, Takamori
Takada-Takatori, Yuki
Akaike, Akinori
Kume, Toshiaki
Author's alias: 泉, 安彦
久米, 利明
Keywords: Nrf2-ARE pathway
Oxidative stress
Parkinson disease
Proteasome activity
Issue Date: 1-Nov-2015
Publisher: Japanese Pharmacological Society
Journal title: Journal of Pharmacological Sciences
Volume: 129
Start page: 150
End page: 159
Abstract: Oxidative stress and the ubiquitin-proteasome system play a key role in the pathogenesis of Parkinson disease. Although the herbicide paraquat is an environmental factor that is involved in the etiology of Parkinson disease, the role of 26S proteasome in paraquat toxicity remains to be determined. Using PC12 cells overexpressing a fluorescent protein fused to the proteasome degradation signal, we report here that paraquat yielded an inhibitory effect on 26S proteasome activity without an obvious decline in 20S proteasome activity. Relative low concentrations of proteasome inhibitors caused the accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2), which is targeted to the ubiquitin-proteasome system, and activated the antioxidant response element (ARE)-dependent transcription. Paraquat also upregulated the protein level of Nrf2 without increased expression of Nrf2 mRNA, and activated the Nrf2-ARE pathway. Consequently, paraquat induced expression of Nrf2-dependent ARE-driven genes, such as γ-glutamylcysteine synthetase, catalase, and hemeoxygenase-1. Knockdown of Nrf2 or inhibition of γ-glutamylcysteine synthetase and catalase exacerbated paraquat-induced toxicity, whereas suppression of hemeoxygenase-1 did not. These data indicate that the compensatory activation of the Nrf2-ARE pathway via inhibition of 26S proteasome serves as part of a cellular defense mechanism to protect against paraquat toxicity.
Rights: © 2015 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society. This is an open access article under the CC BY-NC-ND license ( licenses/by-nc-nd/4.0/).
DOI(Published Version): 10.1016/j.jphs.2015.09.003
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