The Conserved SKN-1/Nrf2 Stress Response Pathway Regulates Synaptic Function in Caenorhabditis elegans

The nrf family of transcription factors plays a critical role in mediating adaptive responses to cellular stress and defends against neurodegeneration,aging,and cancer. here,we report a novel role for the caenorhabditis elegans nrf homolog skn-1 in regulating synaptic transmission at neuromuscular junctions (nmjs). activation of skn-1,either by acute pharmacological treatment with the mitochondrial toxin sodium arsenite or by mutations that cause constitutive skn-1 activation,results in defects in neuromuscular function. additionally,elimination of the conserved wd40 repeat protein wdr-23,a principal negative regulator of skn-1,results in impaired locomotion and synaptic vesicle and neuropeptide release from cholinergic motor axons. mutations that abolish skn-1 activity restore normal neuromuscular function to wdr-23 mutants and animals treated with toxin. we show that negative regulation of skn-1 by wdr-23 in the intestine,but not at neuromuscular junctions,is necessary and sufficient for proper neuromuscular function. wdr-23 isoforms differentially localize to the outer membranes of mitochondria and to nuclei,and the effects of wdr-23 on neuromuscular function are dependent on its interaction with cullin e3 ubiquitin ligase. finally,whole-transcriptome rna sequencing of wdr-23 mutants reveals an increase in the expression of known skn-1/nrf2-regulated stress-response genes,as well as neurotransmission genes not previously implicated in skn-1/nrf2 responses. together,our results indicate that skn-1/nrf2 activation may be a mechanism through which cellular stress,detected in one tissue,affects cellular function of a distal tissue through endocrine signaling. these results provide insight into how skn-1/nrf2 might protect the nervous system from damage in response to oxidative stress. © 2013 staab et al.