Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease, with an average life expectancy of 2–5 years after diagnosis and no available cures. We have discovered a novel mechanism to reduce insoluble TDP-43 aggregates, a toxic protein found across ALS cases. Our in vivo studies show that reducing NLK levels decreases toxic TDP-43, improves motor function, and extends survival in ALS mouse models. Using the Blavatnik Accelerator Award, we developed a class of novel small molecule NLK inhibitors. We are seeking additional funds to advance these candidates in our small molecule development pipeline, which will include safety, selectivity, and in vivo efficacy assessments.