Although our data does not support the seeding of endogenous FUS by the mutant, aberrant interactions of mutant hFUS with other factors could underlie its toxicity, and the ALS-FUS models we present offer a highly disease-relevant, in vivo system in which to explore these interactions and to elucidate mutant FUS-dependent mechanisms of disease. Here, FUS is linked to amyotrophic lateral sclerosis.