Rats expressing human cytosolic copper-zinc superoxide dismutase transgenes with amyotrophic lateral sclerosis: Associated mutations develop motor neuron disease

Some cases of familial amyotrophic lateral sclerosis (ALS) are caused by mu tations in the gene encoding cytosolic, copper-zinc superoxide dismutase (S OD1). 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. As in the human disease and transgenic A LS mice, pathological analysis demonstrates selective loss of motor neurons in the spinal cords of these transgenic rats. In spinal cord tissues, this is accompanied by activation of apoptotic genes known to be activated by m utant SOD1 protein in vitro and in vivo. These animals provide additional s upport for the proposition that motor neuron death in SOD1-related ALS refl ects one or more acquired, neurotoxic properties of the mutant SOD1 protein . The larger size of this rat model as compared with the ALS mice will faci litate studies involving manipulations of spinal fluid (implantation of int rathecal catheters for chronic therapeutic studies; CSF sampling) and spina l cord (e.g., direct administration of viral- and cell-mediated therapies).