Chemical stress induces the unfolded protein response in olfactory sensory neurons

More than any other neuron, olfactory sensory neurons are exposed to environmental insults. Surprisingly, their only documented response to damaging stress is apoptosis and subsequent replacement by new neurons. However, they expressed unfolded protein response genes, a transcriptionally regulated defense mechanism activated by many types of insults. The unfolded protein response transcripts Xbp1, spliced Xbp1, Chop (Ddit3), and BiP (Hspa5) were decreased when external access of stressors was reduced by blocking a nostril (naris occlusion). These transcripts and Nrf2 (Nfe2I2) were increased by systemic application of tunicamycin or the selective olfactotoxic chemical methimazole. Methimazole's effects overcame naris occlusion, and the unfolded protein response was independent of odor-evoked neuronal activity. Chemical stress is therefore a major and chronic activator of the unfolded protein response in olfactory sensory neurons. Stress-dependent repression of the antiapoptotic gene Bcl2 was absent, however, suggesting a mechanism for disconnecting the UPR from apoptosis and tolerating a chronic unfolded protein response. Environmental stressors also affect both the sustentacular cells that support the neurons and the respiratory epithelia, because naris occlusion decreased expression of the xenobiotic chemical transformation enzyme Cyp2a5 in sustentacular cells, and both naris occlusion and methimazole altered the abundance of the antibacterial lectin Reg3g in respiratory epithelia.