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Keap1-Nrf2 activation in the presence and absence of DJ-1

Authors

  • Li Gan,

    1. School of Pharmacy, 6125 Rennebohm Hall, University of Wisconsin–Madison, Madison, WI 53705-2222, USA
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  • Delinda A. Johnson,

    1. School of Pharmacy, 6125 Rennebohm Hall, University of Wisconsin–Madison, Madison, WI 53705-2222, USA
    2. Molecular and Environmental Toxicology Center, University of Wisconsin–Madison, Madison, WI, USA
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  • Jeffrey A. Johnson

    1. School of Pharmacy, 6125 Rennebohm Hall, University of Wisconsin–Madison, Madison, WI 53705-2222, USA
    2. Molecular and Environmental Toxicology Center, University of Wisconsin–Madison, Madison, WI, USA
    3. Waisman Center, University of Wisconsin–Madison, Madison, WI, USA
    4. Center of Neuroscience, University of Wisconsin–Madison, Madison, WI, USA
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Professor Jeffrey A. Johnson, 1School of Pharmacy, as above.
E-mail: jajohnson@pharmacy.wisc.edu

Abstract

The molecular mechanisms leading to neurodegeneration in Parkinson’s disease remain elusive. Deletion and mutations of DJ-1 (PARK7) have been reported to cause autosomal recessive familial Parkinson’s disease. Wildtype DJ-1 scavenges H2O2 by cysteine oxidation in response to oxidative stress, and thus confers neuroprotection. Activation of the transcription factor NF-E2-related factor-2 (Nrf2) has also been shown to be important for protection against oxidative stress in many models of neurodegenerative diseases. Previous data indicate that DJ-1 affects the transcriptional functions and stability of Nrf2. However, this observation has not been confirmed. In the current study, the role of DJ-1 in the regulation of Nrf2 is examined in primary cultured neurons, astrocytes and in vivo. The prototypical Nrf2 activator tBHQ protected primary cortical neurons derived from DJ-1-knockout (KO) as well as DJ-1 wildtype mice by activation of Nrf2-ARE pathway. Nrf2 nuclear translocation, robust increases in canonical Nrf2-driven genes and proteins, and dramatic activation of the ARE reporter gene, hPAP, were observed after tBHQ treatment. These results were further confirmed by siRNA-mediated DJ-1 knockdown in primary cortical astrocytes from ARE-hPAP mice and tBHQ administration into the striatum of mouse brain. In addition, overexpression of Nrf2 with adenovirus preferentially in astrocytes from DJ-1-KO mice enhanced survival of neurons under oxidative insults. These findings indicate that activation of the Nrf2–ARE pathway is independent of DJ-1, and Nrf2 activation is a potential therapeutic target to prevent neurodegeneration in sporadic and DJ-1 familial Parkinson’s disease.

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