We have now generated humanized FUS mice in which the full-length human FUS gene, encoding wild-type or ALS-linked mutations, replaces murine Fus. With expression levels close to the normal levels of endogenous FUS, wild-type or mutant FUS mimics the predominantly nuclear localization of endogenous FUS and complements its essential function(s). Here, FUS is linked to amyotrophic lateral sclerosis.