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
Affiliations
Mandy Koopman
European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Lale Güngördü
European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Leen Janssen
European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Renée I. Seinstra
European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Janet E. Richmond
Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL 60607, USA
Nathan Okerlund
Howard Hughes Medical Institute and School of Biological Science, The University of Utah, Salt Lake City, UT, USA
René Wardenaar
European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Priota Islam
MRC London Institute of Medical Sciences, London, UK; Institute of Clinical Sciences, Imperial College London, London, UK
Wytse Hogewerf
European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Andre E.X. Brown
MRC London Institute of Medical Sciences, London, UK; Institute of Clinical Sciences, Imperial College London, London, UK
Erik M. Jorgensen
Howard Hughes Medical Institute and School of Biological Science, The University of Utah, Salt Lake City, UT, USA
Ellen A.A. Nollen
European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Corresponding author
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.
