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.

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.