Amyotrophic lateral sclerosis (ALS) is a widespread neurodegenerative disease caused by the loss of neurons that control movement. Although abnormal accumulation of proteins called TDP-43 accompanies ALS, its role in disease progression is not well understood. Recently, using novel mouse models of ALS, researchers have identified the neurological spreading patterns through which TDP-43 perpetuates the degeneration of the movement-related neural circuitry.