Familial amyotrophic lateral sclerosis has been linked in 15% of families to mutations in the gene encoding for copper-zinc superoxide dismutase (Cu/Zn-SOD), a key enzyme in the cellular defense mechanisms against free radical attack. We used a transgenic mouse model of familial amyotrophic lateral sclerosis (transgenic G1H mice) based on expression of mutant human Cu/Zn-SOD to examine the influence of the transgene expression on midbrain dopaminergic neurons, cells that contain conspicuous amounts of this enzyme. At the time that 50% of motor neurons of the spinal cord were lost, we observed concurrent reductions in dopamine levels in the caudate-putamen and the nucleus accumbens of transgenic G1H mice. In addition, numbers of tyrosine hydroxylase-immunostained neurons were significantly reduced in both the substantia nigra (26%) and the ventral tegmental area (16%) compared to those in their nontransgenic littermates. Similar abnormalities were not observed in the brains of transgenic mice overexpressing wild-type Cu/Zn-SOD. These findings indicate that overexpression of the mutated Cu/Zn-SOD protein caused a significant loss of midbrain dopaminergic neurons in addition to the loss of spinal motor neurons. The potential of the mutated enzyme to induce cell death extending beyond the motor neurons is consistent with the description of substantia nigra degeneration in some patients with familial amyotrophic lateral sclerosis. Furthermore, if mutated Cu/Zn-SOD is conclusively shown to kill cells by oxidative stress, such an observation would be in keeping with the known sensitivity of dopaminergic neurons to free radical attack.