Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disorder in which the neuromuscular junction progressively degenerates, leading to movement difficulties, paralysis, and eventually death. Often, the translation of preclinical findings to bedside terminates prematurely as the evaluation of potential therapeutic compounds focuses on a single study or a single animal model. To circumscribe these issues, we screened 3,765 novel small molecule derivatives of Pimozide, a recently identified repurposed neuroleptic for ALS, in Caenorhabditis elegans. TRVA242 was identified as the most potent compound as it significantly improved efficiency in rescuing locomotor, motorneuron, and neuromuscular junction synaptic deficits in a C. elegans TDP-43 model.
Methods
Age-synchronized young adult mTDP-43 transgenic worms were distributed in 96-well plate in M9 buffer (20μl per well, approximately 60 worms per well), containing DMSO or test compounds. The swimming activity of the nematodes was measured by a WMicrotracker machine. Experiments were done in triplicate. All positively acting compounds were retested. The experiments were conducted at 20°C. Significance was determined using a two-way ANOVA with multiple comparison post hoc analysis (GraphPad Prism).
Results
We investigated whether TRVA242 could suppress motor neuron phenotypes in our ALS models. In the C. elegans model, we observed that TRVA242 improved the swimming activity of mTDP-43 transgenic worms when tested in liquid culture (Fig. 5A).
Neurotherapeutics . 2019 Oct;16(4):1149-1166. doi: 10.1007/s13311-019-00765-w.
Bose P, Tremblay E, Maois C, Narasimhan V, Armstrong GAB, Liao M, Parker JA, Robitaille R, Wen XY, Barden C, Drapeau P.