title: Loss of nuclear factor E2-related factor 1 in the brain leads to dysregulation of proteasome gene expression and neurodegeneration.
abstract: 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.
authors.affiliation: Department of Laboratory Medicine and Pathology, University of California, Irvine, CA 92697, USA.
authors.forename: Candy S
authors.initials: CS
authors.lastname: Lee
authors.forename: Chiashan
authors.initials: C
authors.lastname: Lee
authors.forename: Terry
authors.initials: T
authors.lastname: Hu
authors.forename: Janice M
authors.initials: JM
authors.lastname: Nguyen
authors.forename: Jiasheng
authors.initials: J
authors.lastname: Zhang
authors.forename: Maureen V
authors.initials: MV
authors.lastname: Martin
authors.forename: Marquis P
authors.initials: MP
authors.lastname: Vawter
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Huang
authors.forename: Jefferson Y
authors.initials: JY
authors.lastname: Chan
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D005786:Gene Expression Regulation; D051379:Mice; D051265:NF-E2-Related Factor 1 / Q000172:deficiency / Q000378:metabolism*; D009410:Nerve Degeneration / Q000209:etiology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000235:genetics*
chemical_list: D051265:NF-E2-Related Factor 1; D046988:Proteasome Endopeptidase Complex