Rebalancing the motor circuit restores movement in a Caenorhabditis elegans model for TDP-43 toxicity

Autor: Mandy Koopman, Lale Güngördü, Leen Janssen, Renée I. Seinstra, Janet E. Richmond, Nathan Okerlund, René Wardenaar, Priota Islam, Wytse Hogewerf, Andre E.X. Brown, Erik M. Jorgensen, Ellen A.A. Nollen
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: Cell Reports, Vol 43, Iss 5, Pp 114204- (2024)
Druh dokumentu: article
ISSN: 2211-1247
DOI: 10.1016/j.celrep.2024.114204
Popis: Summary: 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.
Databáze: Directory of Open Access Journals