We provide genetic evidence that, despite a partial loss of function associated with the equivalents of the human FUSP525L mutation (mFusP517L) and a truncation mutation (G466VfsX14 or Δ14) associated with rapidly progressive, juvenile-onset ALS15, expression of these mutant forms of FUS in vivo at physiological levels leads to progressive, age-dependent MN degeneration that is dose dependent and selective for MN subpopulations known to be preferentially vulnerable in patients with ALS and related mouse models of familial ALS. The gene discussed is FUS; the disease is amyotrophic lateral sclerosis.