Limited Expression ofNrf2in Neurons Across the Central Nervous System

Nrf2 is a broadly expressed transcription factor that regulates gene expression in response to reactive oxygen species (ROS) and oxidative stress. It is commonly referred to as a ubiquitous pathway, but this generalization overlooks work indicating that Nrf2 is essentially unexpressed in some neuronal populations. To explore whether this pattern extends throughout the central nervous system (CNS), we quantifiedNrf2expression and chromatin accessibility at theNrf2locus across multiple single cell datasets. In both the mouse and human CNS,Nrf2was repressed in almost all mature neurons, but highly expressed in non-neuronal support cells, and this pattern was robust across multiple human CNS diseases. A subset of key Nrf2 target genes, likeSlc7a11, also remained low in neurons. Thus, these data suggest that while most cells express Nrf2, with activity determined by ROS levels, neurons actively avoid Nrf2 activity by keepingNrf2expression low.