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

Research output: Chapter in Book/Report/Conference proceedingConference contribution

335 Citations (Scopus)

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.

Original languageEnglish
Title of host publicationMitochondria and Oxidative Stress in Neurodegenerative Disorders
PublisherBlackwell Publishing Inc.
Pages61-69
Number of pages9
ISBN (Print)9781573317139
DOIs
Publication statusPublished - 2008 Dec

Publication series

NameAnnals of the New York Academy of Sciences
Volume1147
ISSN (Print)0077-8923
ISSN (Electronic)1749-6632

Fingerprint

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

Cite this

Johnson, J. A., Johnson, D. A., Kraft, A. D., Calkins, M. J., Jakel, R. J., Vargas, M. R., & Chen, P. C. (2008). The Nrf2-ARE pathway: An indicator and modulator of oxidative stress in neurodegeneration. In Mitochondria and Oxidative Stress in Neurodegenerative Disorders (pp. 61-69). (Annals of the New York Academy of Sciences; Vol. 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. pp. 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.",
author = "Johnson, {Jeffrey A.} and Johnson, {Delinda A.} and Kraft, {Andrew D.} and Calkins, {Marcus J.} and Jakel, {Rebekah J.} and Vargas, {Marcelo R.} and Chen, {Pei Chun}",
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Johnson, JA, Johnson, DA, Kraft, AD, Calkins, MJ, Jakel, RJ, Vargas, MR & Chen, PC 2008, The Nrf2-ARE pathway: An indicator and modulator of oxidative stress in neurodegeneration. in Mitochondria and Oxidative Stress in Neurodegenerative Disorders. Annals of the New York Academy of Sciences, vol. 1147, Blackwell Publishing Inc., pp. 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; Vol. 1147).

Research output: Chapter in Book/Report/Conference proceedingConference contribution

TY - GEN

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.

AU - Jakel, Rebekah J.

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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T3 - Annals of the New York Academy of Sciences

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Johnson JA, Johnson DA, Kraft AD, Calkins MJ, Jakel RJ, Vargas MR et al. The Nrf2-ARE pathway: An indicator and modulator of oxidative stress in neurodegeneration. In 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