oaioai:www.repository.cam.ac.uk:1810/299545

Exploring the role of the unfolded protein response in C. elegans neurons

Abstract

The nervous system of C. elegans plays a role in the orchestration of systemic stress responses. One of these stress responses, the unfolded protein response of the endoplasmic reticulum (UPRER), is activated to re-establish protein homeostasis (proteostasis) upon the detection of ER stress. Overexpression of active, spliced XBP-1 (XBP-1s), a transcription factor that acts downstream of the UPRER kinase/endoribonuclease IRE-1, in the nervous system of C. elegans increases the lifespan and healthspan of worms through UPRER induction in the intestine cell non-autonomously. To investigate XBP-1s-dependent changes in the nervous system of these animals, we conducted tissue-specific RNA-Seq in neurons. This approach allowed us to characterise differentially regulated neuronal and synaptic components, which may mediate changes to the nervous system that cause the release of inter-tissue UPRER-activating signals. Furthermore, we extended our tissue-specific RNA-Seq analyses to the intestine, using intestinal cells from neuronal xbp-1s- or intestinal xbp-1s-overexpressing worms. We identified lysosomal gene upregulation in the intestine, which leads to activation of intestinal lysosomes downstream of neuronal xbp-1s. Moreover, comparison of cell autonomous and cell non-autonomous targets of XBP-1s within the intestine showed that XBP-1s has different but overlapping sets of target genes via different activation mechanisms. We also employed a candidate screening approach based on our previous finding that neurotransmitter secretion is required for intestinal UPRER activation upon neuronal xbp-1s overexpression, and identified positive and negative regulators of intestinal UPRER activation. This showed that distal UPRER activation relies on tyramine/octopamine production, and is modulated by the worm TGF-β homologue DAF-7. We then asked whether neuronal xbp-1s can affect other systemic outputs requiring neuron-specific functions, such as the regulation of behaviour. We found that a branch of the neuronal circuitry required to activate UPRER in the intestine following neuronal XBP-1s overexpression is also required to generate neuronal xbp-1s-dependent behavioural phenotypes in food-leaving and reproduction. These findings suggest that inter-tissue UPRER activation, increased longevity and healthspan can be coordinately regulated with stress-responsive behaviour by the activation of XBP-1s in the nervous system.LMB Cambridge Scholarshi

Similar works

Full text

thumbnail-image
oaioai:www.repository.cam.ac.uk:1810/299545Last time updated on 12/13/2019

This paper was published in Apollo.

Having an issue?

Is data on this page outdated, violates copyrights or anything else? Report the problem now and we will take corresponding actions after reviewing your request.