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UNC-49 is a redox-sensitive GABAA receptor that regulates the mitochondrial unfolded protein response cell nonautonomously.

Pohl, Franziska; Germann, Allison L.; Mao, Jack; Hou, Sydney; Bakare, Bayode; Kong Thoo Lin, Paul; Yates, Kyari; Nonet, Michael L.; Akk, Gustav; Kornfeld, Kerry; Held, Jason M.

Authors

Franziska Pohl

Allison L. Germann

Jack Mao

Sydney Hou

Bayode Bakare

Michael L. Nonet

Gustav Akk

Kerry Kornfeld

Jason M. Held



Abstract

The γ-aminobutyric acid–mediated (GABAergic) system participates in many aspects of organismal physiology and disease, including proteostasis, neuronal dysfunction and life-span extension. Many of these phenotypes are also regulated by reactive oxygen species (ROS), but the redox mechanisms linking the GABAergic system to these phenotypes are not well defined. Here, we report that GABAergic redox signaling cell nonautonomously activates many stress response pathways in Caenorhabditis elegans and enhances vulnerability to proteostasis disease in the absence of oxidative stress. Cell nonautonomous redox activation of the mitochondrial unfolded protein response (mitoUPR) proteostasis network requires UNC-49, a GABAA receptor that we show is activated by hydrogen peroxide. MitoUPR induction by a spinocerebellar ataxia type 3 (SCA3) C. elegans neurodegenerative disease model was similarly dependent on UNC-49 in C. elegans. These results demonstrate a multi-tissue paradigm for redox signaling in the GABAergic system that is transduced via a GABAA receptor to function in cell nonautonomous regulation of health, proteostasis and disease.

Citation

POHL, F., GERMANN, A.L., MAO, J., HOU, S., BAKARE, B., KONG THOO LIN, P., YATES, K., NONET, M.L., AKK, G., KORNFELD, K. and HELD, J.M. 2023. UNC-49 is a redox-sensitive GABAA receptor that regulates the mitochondrial unfolded protein response cell nonautonomously. Science advances [online], 9(44). Available from: https://doi.org/10.1126/sciadv.adh2584

Journal Article Type Article
Acceptance Date Sep 21, 2023
Online Publication Date Nov 1, 2023
Publication Date Nov 30, 2023
Deposit Date Nov 3, 2023
Publicly Available Date Nov 3, 2023
Journal Science advances
Electronic ISSN 2375-2548
Publisher American Association for the Advancement of Science
Peer Reviewed Peer Reviewed
Volume 9
Issue 44
DOI https://doi.org/10.1126/sciadv.adh2584
Keywords Reactive oxygen species (ROS); Synaptic neurotransmission; GABAergic system
Public URL https://rgu-repository.worktribe.com/output/2086112
PMID 37910615
Additional Information The attached file includes both the published article and accompanying supplementary materials.