Nrf2 Week #2: Neurons

To follow the Nrf2 Week #1 suggestion that Nrf2 target neurological disorders, this 2023 cell study investigated Nrf2 expression in neurons:

“Oxidative metabolism is inextricably linked to production of reactive oxygen species (ROS), which have the potential to damage all classes of macromolecules. Yet ROS are not invariably detrimental. Several properties make ROS useful signaling molecules, including their potential for rapid modification of proteins and close ties to cellular metabolism.

We used multiple single cell genomic datasets to explore Nrf2 expression and regulation in hundreds of neuronal and non-neuronal cell types in mouse and human. With few exceptions, Nrf2 is expressed at far lower levels in neurons than in non-neuronal support cells in both species.

This pattern is maintained in multiple disease states, and the chromatin accessibility landscape at the Nrf2 locus parallels these expression differences. These results imply that Nrf2 activity is limited in almost all neurons of the mouse and human central nervous system (CNS).

nrf2 expression

We separated cell types into neuron or non-neuronal ‘support’ cell categories. The general ‘support’ term is not meant to minimize the functional relevance of non-neuronal cells in the CNS, but is an umbrella term meant to cover everything from glial cell types (astrocytes, microglia, oligodendrocytes) to endothelial cells.

It is not clear why an important, near ubiquitous cytoprotective transcription factor like Nrf2 remains off in mature neurons, especially considering oxidative stress is a driver of many diseases. The simplest explanation is that Nrf2 activity also disrupts normal function of mature neurons.

ROS play a key role in controlling synaptic plasticity in mature neurons. These activity-dependent changes in synaptic transmission, which are important for learning and memory, are disrupted by antioxidants.

A subset of important Nrf2-targeted antioxidant genes (e.g., Slc3a2, Slc7a11, Nqo1, Prdx1) are also low in neurons. So it is likely that these and/or other Nrf2 targets must remain low or non-ROS-responsive in mature neurons. Future work exploring why this expression pattern persists in mature neurons will inform our models on roles of antioxidant genes in normal neuronal physiology and in neurological disorders. “Limited Expression of Nrf2 in Neurons Across the Central Nervous System”



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