European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL 60607, USA.
Cell Rep. 2024 May 28;43(5):114204. doi: 10.1016/j.celrep.2024.114204. Epub 2024 May 14.
Amyotrophic lateral sclerosis can be caused by abnormal accumulation of TAR DNA-binding protein 43 (TDP-43) in the cytoplasm of neurons. Here, we use a C. elegans model for TDP-43-induced toxicity to identify the biological mechanisms that lead to disease-related phenotypes. By applying deep behavioral phenotyping and subsequent dissection of the neuromuscular circuit, we show that TDP-43 worms have profound defects in GABA neurons. Moreover, acetylcholine neurons appear functionally silenced. Enhancing functional output of repressed acetylcholine neurons at the level of, among others, G-protein-coupled receptors restores neurotransmission, but inefficiently rescues locomotion. Rebalancing the excitatory-to-inhibitory ratio in the neuromuscular system by simultaneous stimulation of the affected GABA- and acetylcholine neurons, however, not only synergizes the effects of boosting individual neurotransmitter systems, but instantaneously improves movement. Our results suggest that interventions accounting for the altered connectome may be more efficient in restoring motor function than those solely focusing on diseased neuron populations.
肌萎缩性侧索硬化症可能是由神经元细胞质中 TAR DNA 结合蛋白 43（TDP-43）的异常积累引起的。在这里，我们使用 C. elegans 模型来研究 TDP-43 诱导的毒性，以确定导致疾病相关表型的生物学机制。通过应用深度行为表型分析以及随后对神经肌肉回路的剖析，我们发现 TDP-43 线虫的 GABA 神经元存在严重缺陷。此外，乙酰胆碱神经元似乎功能沉默。在 G 蛋白偶联受体等水平上增强受抑制的乙酰胆碱神经元的功能输出可以恢复神经传递，但不能有效地恢复运动。然而，通过同时刺激受影响的 GABA 神经元和乙酰胆碱神经元来重新平衡神经肌肉系统中的兴奋性-抑制性比率，不仅可以协同增强单个神经递质系统的作用，而且可以立即改善运动。我们的研究结果表明，与仅针对患病神经元群体的干预措施相比，考虑到改变的连接组的干预措施可能更有效地恢复运动功能。
