The Nrf2-ARE pathway: An indicator and modulator of oxidative stress in neurodegeneration

Jeffrey A. Johnson, Delinda A. Johnson, Andrew D. Kraft, Marcus J. Calkins, Rebekah J. Jakel, Marcelo R. Vargas, Pei-chun Chen

研究成果: Conference contribution

335 引文 (Scopus)

摘要

Transcriptional activation of protective genes is mediated by a cis-acting element called the antioxidant responsive element (ARE). The transcription factor Nrf2 (NF-E2-related factor 2) binds to the ARE. Activation of this pathway protects cells from oxidative stress-induced cell death. Increased oxidative stress is associated with neuronal cell death during the pathogenesis of multiple chronic neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. We hypothesize that Nrf2-ARE activation is a novel neuroprotective pathway that confers resistance to a variety of oxidative, stress-related, neurodegenerative insults. In recent studies, primary neuronal cultures treated with chemical activators of the Nrf2-ARE pathway displayed significantly greater resistance to oxidative stress-induced neurotoxicity. Similar cultures generated from ARE-hPAP reporter mice demonstrated selective activation of the Nrf2-ARE pathway in astrocytes, suggesting that Nrf2 activation in astrocytes somehow confers resistance to naive neurons. Further, in chemical models of neurodegeneration, Nrf2 knockout mice are significantly more sensitive to mitochondrial complex I and II inhibitors. Combining these observations with the results implying that the astrocyte is central to Nrf2-ARE-mediated neuroprotection, we transplanted Nrf2-overexpressing astrocytes into the mouse striatum prior to lesioning with malonate. This procedure led to dramatic protection against malonate-induced neurotoxicity. Translating this to other chemical and genetic models of neurodegeneration will be discussed.

原文English
主出版物標題Mitochondria and Oxidative Stress in Neurodegenerative Disorders
發行者Blackwell Publishing Inc.
頁面61-69
頁數9
ISBN(列印)9781573317139
DOIs
出版狀態Published - 2008 一月 1

出版系列

名字Annals of the New York Academy of Sciences
1147
ISSN(列印)0077-8923
ISSN(電子)1749-6632

指紋

NF-E2-Related Factor 2
Oxidative stress
Modulators
Oxidative Stress
Antioxidants
Astrocytes
Chemical activation
Chemical Models
Cell death
Cell Death
Neurodegenerative diseases
Transcription factors
Activation
Pathway
Genetic Models
Huntington Disease
Amyotrophic Lateral Sclerosis
Knockout Mice
Neurodegenerative Diseases
Transcriptional Activation

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

引用此文

Johnson, J. A., Johnson, D. A., Kraft, A. D., Calkins, M. J., Jakel, R. J., Vargas, M. R., & Chen, P. (2008). The Nrf2-ARE pathway: An indicator and modulator of oxidative stress in neurodegeneration. 於 Mitochondria and Oxidative Stress in Neurodegenerative Disorders (頁 61-69). (Annals of the New York Academy of Sciences; 卷 1147). Blackwell Publishing Inc.. https://doi.org/10.1196/annals.1427.036
Johnson, Jeffrey A. ; Johnson, Delinda A. ; Kraft, Andrew D. ; Calkins, Marcus J. ; Jakel, Rebekah J. ; Vargas, Marcelo R. ; Chen, Pei-chun. / The Nrf2-ARE pathway : An indicator and modulator of oxidative stress in neurodegeneration. Mitochondria and Oxidative Stress in Neurodegenerative Disorders. Blackwell Publishing Inc., 2008. 頁 61-69 (Annals of the New York Academy of Sciences).
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abstract = "Transcriptional activation of protective genes is mediated by a cis-acting element called the antioxidant responsive element (ARE). The transcription factor Nrf2 (NF-E2-related factor 2) binds to the ARE. Activation of this pathway protects cells from oxidative stress-induced cell death. Increased oxidative stress is associated with neuronal cell death during the pathogenesis of multiple chronic neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. We hypothesize that Nrf2-ARE activation is a novel neuroprotective pathway that confers resistance to a variety of oxidative, stress-related, neurodegenerative insults. In recent studies, primary neuronal cultures treated with chemical activators of the Nrf2-ARE pathway displayed significantly greater resistance to oxidative stress-induced neurotoxicity. Similar cultures generated from ARE-hPAP reporter mice demonstrated selective activation of the Nrf2-ARE pathway in astrocytes, suggesting that Nrf2 activation in astrocytes somehow confers resistance to naive neurons. Further, in chemical models of neurodegeneration, Nrf2 knockout mice are significantly more sensitive to mitochondrial complex I and II inhibitors. Combining these observations with the results implying that the astrocyte is central to Nrf2-ARE-mediated neuroprotection, we transplanted Nrf2-overexpressing astrocytes into the mouse striatum prior to lesioning with malonate. This procedure led to dramatic protection against malonate-induced neurotoxicity. Translating this to other chemical and genetic models of neurodegeneration will be discussed.",
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Johnson, JA, Johnson, DA, Kraft, AD, Calkins, MJ, Jakel, RJ, Vargas, MR & Chen, P 2008, The Nrf2-ARE pathway: An indicator and modulator of oxidative stress in neurodegeneration. 於 Mitochondria and Oxidative Stress in Neurodegenerative Disorders. Annals of the New York Academy of Sciences, 卷 1147, Blackwell Publishing Inc., 頁 61-69. https://doi.org/10.1196/annals.1427.036

The Nrf2-ARE pathway : An indicator and modulator of oxidative stress in neurodegeneration. / Johnson, Jeffrey A.; Johnson, Delinda A.; Kraft, Andrew D.; Calkins, Marcus J.; Jakel, Rebekah J.; Vargas, Marcelo R.; Chen, Pei-chun.

Mitochondria and Oxidative Stress in Neurodegenerative Disorders. Blackwell Publishing Inc., 2008. p. 61-69 (Annals of the New York Academy of Sciences; 卷 1147).

研究成果: Conference contribution

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T1 - The Nrf2-ARE pathway

T2 - An indicator and modulator of oxidative stress in neurodegeneration

AU - Johnson, Jeffrey A.

AU - Johnson, Delinda A.

AU - Kraft, Andrew D.

AU - Calkins, Marcus J.

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AU - Vargas, Marcelo R.

AU - Chen, Pei-chun

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N2 - Transcriptional activation of protective genes is mediated by a cis-acting element called the antioxidant responsive element (ARE). The transcription factor Nrf2 (NF-E2-related factor 2) binds to the ARE. Activation of this pathway protects cells from oxidative stress-induced cell death. Increased oxidative stress is associated with neuronal cell death during the pathogenesis of multiple chronic neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. We hypothesize that Nrf2-ARE activation is a novel neuroprotective pathway that confers resistance to a variety of oxidative, stress-related, neurodegenerative insults. In recent studies, primary neuronal cultures treated with chemical activators of the Nrf2-ARE pathway displayed significantly greater resistance to oxidative stress-induced neurotoxicity. Similar cultures generated from ARE-hPAP reporter mice demonstrated selective activation of the Nrf2-ARE pathway in astrocytes, suggesting that Nrf2 activation in astrocytes somehow confers resistance to naive neurons. Further, in chemical models of neurodegeneration, Nrf2 knockout mice are significantly more sensitive to mitochondrial complex I and II inhibitors. Combining these observations with the results implying that the astrocyte is central to Nrf2-ARE-mediated neuroprotection, we transplanted Nrf2-overexpressing astrocytes into the mouse striatum prior to lesioning with malonate. This procedure led to dramatic protection against malonate-induced neurotoxicity. Translating this to other chemical and genetic models of neurodegeneration will be discussed.

AB - Transcriptional activation of protective genes is mediated by a cis-acting element called the antioxidant responsive element (ARE). The transcription factor Nrf2 (NF-E2-related factor 2) binds to the ARE. Activation of this pathway protects cells from oxidative stress-induced cell death. Increased oxidative stress is associated with neuronal cell death during the pathogenesis of multiple chronic neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. We hypothesize that Nrf2-ARE activation is a novel neuroprotective pathway that confers resistance to a variety of oxidative, stress-related, neurodegenerative insults. In recent studies, primary neuronal cultures treated with chemical activators of the Nrf2-ARE pathway displayed significantly greater resistance to oxidative stress-induced neurotoxicity. Similar cultures generated from ARE-hPAP reporter mice demonstrated selective activation of the Nrf2-ARE pathway in astrocytes, suggesting that Nrf2 activation in astrocytes somehow confers resistance to naive neurons. Further, in chemical models of neurodegeneration, Nrf2 knockout mice are significantly more sensitive to mitochondrial complex I and II inhibitors. Combining these observations with the results implying that the astrocyte is central to Nrf2-ARE-mediated neuroprotection, we transplanted Nrf2-overexpressing astrocytes into the mouse striatum prior to lesioning with malonate. This procedure led to dramatic protection against malonate-induced neurotoxicity. Translating this to other chemical and genetic models of neurodegeneration will be discussed.

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Johnson JA, Johnson DA, Kraft AD, Calkins MJ, Jakel RJ, Vargas MR 等. The Nrf2-ARE pathway: An indicator and modulator of oxidative stress in neurodegeneration. 於 Mitochondria and Oxidative Stress in Neurodegenerative Disorders. Blackwell Publishing Inc. 2008. p. 61-69. (Annals of the New York Academy of Sciences). https://doi.org/10.1196/annals.1427.036