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

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*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

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    Abstract

    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.

    Original languageEnglish
    Article number114204
    Number of pages27
    JournalCell reports
    Volume43
    Issue number5
    Early online date13-May-2024
    DOIs
    Publication statusPublished - 28-May-2024

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