From cellular vulnerability to altered circuit activity: a systems biology approach to study amyotrophic lateral sclerosis

The devastating effects of the brain losing its ability to control voluntary body movement are illustrated by diseases such as amyotrophic lateral sclerosis (ALS) - where the nerve cells that allow the brain to effectively communicate with muscles are progressively lost. Most of the ALS research traditionally revolves around the affected nerve cells, known as motoneurons, and aims to rescue their decline in function. Motoneurons are however part of larger networks in the nervous system and constantly receive, process and transmit signals. Therefore, even the smallest alteration of a single motoneuron will likely leave a mark on its connecting neurons and vice versa. Could it be that solely targeting the function of diseased neurons has unexpected effects in an already (mal)adapted network? To mimic ALS, we used the worm Caenorhabditis elegans engineered to express the human gene TDP-43. Dysregulated TDP-43 is considered a uniform hallmark of ALS and its expression in C. elegans causes severe paralysis. By developing and combining numerous technology-driven, mostly unbiased screening approaches we show that TDP-43 impedes neuronal function and causes an imbalance between stimulatory and inhibitory signals in the motor circuit. While functional output of repressed motoneurons could be restored via modulation of their activity, these interventions did not result in improved locomotion. Rebalancing the derailed motor circuit dynamics by combining multiple treatments, however, effectively restored movement. Because of the high degree of similarity in genetic alterations and pathology between ALS worms and patients, similar therapeutic strategies may eventually be valuable for ALS patients.