Distinct responses to non-autonomous UPRER mediated by glutamatergic and octopaminergic neurons

Year: 2025

Type: article

Abstract: The capacity to deal with stress declines during the aging process, and preservation of cellular stress responses is critical to healthy aging. The unfolded protein response of the endoplasmic reticulum (UPRER) is one such conserved mechanism, which is critical for the maintenance of several major functions of the ER during stress, including protein folding and lipid metabolism. Hyperactivation of the UPRER by overexpression of the major transcription factor, xbp-1s, solely in neurons drives lifespan extension as neurons send a neurotransmitter-based signal to other tissues to activate UPRER in a non-autonomous fashion. Previous work identified serotonergic, dopaminergic, and tyraminergic neurons in this signaling paradigm. To further expand our understanding of the neural circuitry that underlies the non-autonomous signaling of ER stress, we activated UPRER solely in glutamatergic, octopaminergic, and GABAergic neurons in C. elegans and paired whole-body transcriptomic analysis with functional assays. We found that UPRER-induced signals from glutamatergic neurons increased expression of canonical protein homeostasis pathways and octopaminergic neurons promoted pathogen response pathways, while more modest changes were detected in GABAergic UPRER activation. These findings provide further evidence for the distinct role neuronal subtypes play in driving the diverse response to ER stress. Activation of the UPRER in distinct C. elegans neuronal subtypes drives unique organismal outcomes: glutamatergic neurons enhance proteostasis, octopaminergic neurons boost immune defenses and extend lifespan, while GABAergic neurons show modest effects.

Source: Communications Biology

DOI: 10.1038/s42003-025-09036-1

Authors: Aeowynn J. Coakley, Adam J. Hruby, Jing Wang, Andrew Bong, Tripti Nair, Carmen M. Ramos, Athena Alcala, Daniel Hicks, Maxim Averbukh, Naibedya Dutta, Darius Moaddeli, Camilla Pearson, Cynthia J. Siebrand, Mattias de los Rios Rogers, Arushi Sahay, Sean P. Curran, Peter J. Mullen, Bérénice A. Benayoun, Gilberto Garcia, Ryo Higuchi-Sanabria

Institutions: University of Southern California, Buck Institute for Research on Aging, University of California, Los Angeles, University of Pennsylvania

Language: English

Topic: Genetics, Aging, and Longevity in Model Organisms

Subfield: Aging

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $4,190

Funders: National Science Foundation, U.S. Department of Health and Human Services, Simons Foundation, Glenn Foundation for Medical Research, Donald E. and Delia B. Baxter Foundation, Fondation pour la Recherche Médicale, National Institutes of Health, National Institute on Aging, National Human Genome Research Institute

OpenAlex ID: W4416593268