Mutations in Cu/Zn superoxide dismutase (SOD1) have been linked to some familial cases of amyotrophic lateral sclerosis (ALS). In order to reproduce the different degree of toxicity to the mutant protein by mutations, we generated new transgenic mice with two mutations from which the progression of the disease in human family is rapid (L84V) or extremely slow (H46R). By comparing the two transgenic mice with different SOD1 mutations, we demonstrate that the time course and the first symptoms in these mice were likely to human SOD1-mediated familial ALS. In addition, we report here that rats that express a human SOD1 transgene with two different ALS-associated mutations (G93A and H46R) develop striking motor neuron degeneration and paralysis. The larger size of this rat model as compared with the ALS mice will facilitate studies involving manipulations of spinal fluid (implantation of intrathecal catheters for chronic therapeutic studies; CSF sampling) and spinal cord (e.g., direct administration of viral- and cell-mediated therapies). Using this rat model we showed that intrathecal administration of the hepatocyte growth factor attenuates motoneuron death and prolongs the duration of the disease of transgenic rats.