While a gain-of-function mechanism due to TDP-43 cytoplasmic aggregates has been proposed to contribute to neurodegeneration2–6, emerging evidence supports the idea that loss of TDP-43 repression of cryptic splicing resulting from depletion of nuclear TDP-43 drives neuron loss in ALS–FTD7,8. The gene discussed is TARDBP; the disease is amyotrophic lateral sclerosis.