RRC ID 80958
Author Pohl F, Germann AL, Mao J, Hou S, Bakare B, Kong Thoo Lin P, Yates K, Nonet ML, Akk G, Kornfeld K, Held JM.
Title UNC-49 is a redox-sensitive GABAA receptor that regulates the mitochondrial unfolded protein response cell nonautonomously.
Journal Sci Adv
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.
Volume 9(44)
Pages eadh2584
Published 2023-11-3
DOI 10.1126/sciadv.adh2584
PMID 37910615
PMC PMC10619936
MeSH Animals Caenorhabditis elegans / metabolism Caenorhabditis elegans Proteins* / genetics Caenorhabditis elegans Proteins* / metabolism Neurodegenerative Diseases* Oxidation-Reduction Receptors, GABA-A / metabolism Unfolded Protein Response
C.elegans tm5487