Transgenic mice expressing an H46R mutant of human Cu/Zn superoxide dismutase.

In some cases of familial amyotrophic lateral sclerosis (ALS), mutations of copper-zinc superoxide dismutase (Cu/Zn SOD) are linked to this disease. Several kinds of transgenic (Tg) mice carrying human mutant Cu/Zn SOD have been reported and these mice showed different clinical symptoms and pathological changes. We made new transgenic mice with the H46R mutation because this mutation is located on the active site of Cu/Zn SOD and is associated with extremely slow progression of the disease. We obtained a clone containing an approximately 11.5 kb human Cu/Zn SOD gene from a PAC library and the H46R mutation was engineered by site-directed mutagenesis. The human Cu/Zn SOD gene with the H46R mutation was microinjected into mouse embryos. We made two lines and each had different copies of the mutant human Cu/Zn SOD gene. The Tg mice expressing high copies of mutant Cu/Zn SOD gene showed ALS-like symptoms. The age of the onset was about 150 days and the initial sign was weakened grip strength in one hindlimb. Mice were completely paralyzed within 3-4 weeks after the onset. Although human Cu/Zn SOD protein accumulated in the spinal cord of this Tg mouse, the Cu/Zn SOD activity was reduced compared to non-Tg mice. The pathological study revealed selective neuronal death of motor neurons in the spinal cord.