Development and Stem Cells Program, Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Melbourne, VIC, 3800, Australia.
Nat Commun. 2024 Aug 3;15(1):6594. doi: 10.1038/s41467-024-50973-y.
Neurons coordinate inter-tissue protein homeostasis to systemically manage cytotoxic stress. In response to neuronal mitochondrial stress, specific neuronal signals coordinate the systemic mitochondrial unfolded protein response (UPR) to promote organismal survival. Yet, whether chemical neurotransmitters are sufficient to control the UPR in physiological conditions is not well understood. Here, we show that gamma-aminobutyric acid (GABA) inhibits, and acetylcholine (ACh) promotes the UPR in the Caenorhabditis elegans intestine. GABA controls the UPR by regulating extra-synaptic ACh release through metabotropic GABA receptors GBB-1/2. We find that elevated ACh levels in animals that are GABA-deficient or lack ACh-degradative enzymes induce the UPR through ACR-11, an intestinal nicotinic α7 receptor. This neuro-intestinal circuit is critical for non-autonomously regulating organismal survival of oxidative stress. These findings establish chemical neurotransmission as a crucial regulatory layer for nervous system control of systemic protein homeostasis and stress responses.
神经元协调组织间蛋白质稳态，以系统性地管理细胞毒性应激。在神经元线粒体应激的情况下，特定的神经元信号协调全身线粒体未折叠蛋白反应 (UPR)，以促进生物体的存活。然而，化学神经递质是否足以在生理条件下控制 UPR 尚不清楚。在这里，我们表明γ-氨基丁酸 (GABA) 抑制，而乙酰胆碱 (ACh) 促进秀丽隐杆线虫肠道中的 UPR。GABA 通过调节代谢型 GABA 受体 GBB-1/2 来控制突触外 ACh 的释放来控制 UPR。我们发现，缺乏 GABA 或缺乏 ACh 降解酶的动物中 ACh 水平升高会通过肠道烟碱型 α7 受体 ACR-11 诱导 UPR。这个神经-肠道回路对于非自主调节氧化应激下的生物体存活至关重要。这些发现确立了化学神经传递作为神经系统控制全身蛋白质稳态和应激反应的关键调节层。
