Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 20, Pages 8408-8413Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1019209108
Keywords
oxidative stress; conditional knockout; antioxidant response element
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Funding
- National Institutes of Health [NS065223, MH085801, NS048393, RR024858]
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The ubiquitin-proteasome pathway plays an important role in the pathogenesis of neurodegeneration, but mechanisms controlling expression of components in this pathway remain poorly understood. Nuclear factor E2-related factor 1 (Nrf1) transcription factor has been shown to regulate expression of antioxidant and cytoprotective genes. To determine the function of Nrf1 in the brain, mice with a late-stage deletion of Nrf1 in neuronal cells were generated. Loss of Nrf1 leads to impaired proteasome function and neurodegeneration. Gene expression profiling and RT-PCR analysis revealed a coordinate down-regulation of various proteasomal genes including PsmB6, which encodes a catalytic subunit of the proteasome. Transcriptional analysis and chromatin immunoprecipitation experiments demonstrated that PsmB6 is an Nrf1 target gene. These findings reveal Nrf1 as a key transcriptional regulator required for the expression of proteasomal genes in neurons and suggest that perturbations of Nrf1 function may contribute to the pathogenesis of neurodegenerative diseases.
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