Loss of nuclear factor E2-related factor 1 in the brain leads to dysregulation of proteasome gene expression and neurodegeneration.

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.

PPARδ activation by bexarotene promotes neuroprotection by restoring bioenergetic and quality control homeostasis.

Neurons must maintain protein and mitochondrial quality control for optimal function, an energetically expensive process. The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that promote mitochondrial biogenesis and oxidative metabolism. We recently determined that transcriptional dysregulation of PPARδ contributes to Huntington's disease (HD), a progressive neurodegenerative disorder resulting from a CAG-polyglutamine repeat expansion in the huntingtin gene. We documented that the PPARδ agonist KD3010 is an effective therapy for HD in a mouse model. PPARδ forms a heterodimer with the retinoid X receptor (RXR), and RXR agonists are capable of promoting PPARδ activation. One compound with potent RXR agonist activity is the U.S. Food and Drug Administration-approved drug bexarotene. We tested the therapeutic potential of bexarotene in HD and found that bexarotene was neuroprotective in cellular models of HD, including medium spiny-like neurons generated from induced pluripotent stem cells (iPSCs) derived from patients with HD. To evaluate bexarotene as a treatment for HD, we treated the N171-82Q mouse model with the drug and found that bexarotene improved motor function, reduced neurodegeneration, and increased survival. To determine the basis for PPARδ neuroprotection, we evaluated metabolic function and noted markedly impaired oxidative metabolism in HD neurons, which was rescued by bexarotene or KD3010. We examined mitochondrial and protein quality control in cellular models of HD and observed that treatment with a PPARδ agonist promoted cellular quality control. By boosting cellular activities that are dysfunctional in HD, PPARδ activation may have therapeutic applications in HD and potentially other neurodegenerative diseases.