Multiple missense mutations that substitute one amino acid for another have been found in copper-zinc superoxide dismutase (SOD) in patients with a familial form of amyotrophic lateral sclerosis (ALS). When expressed at high levels in the spinal cord of transgenic mice, mutant human copper-zinc SOD causes progressive loss of motoneurons with consequent paralysis and death. Within the spinal cord, ventral horn motoneurons express the highest levels of mutant human copper-zinc SOD. The mouse model has proved useful for the study of disease mechanisms and for the preclinical studies of potential therapeutics. Neuroprotective agents with benefit in the model include antioxidants, antiglutamatergic agents, and antiapoptotic agents. Most neuroprotective agents either delay disease onset (antioxidants) or extend survival after development of symptomatic disease (antiglutamatergics), suggesting that different mechanisms underlie disease initiation and progression. Profiling of gene expression in transgenic mouse spinal cords shows dysregulation of metal ion homeostasis at end-stage disease; however, a different pattern of gene activation is seen in spinal cords from sporadic ALS. Thus, metal-catalyzed damage by oxygen free radicals may be a feature of the transgenic model but not of sporadic ALS.
Gurney ME. Preclinical Evaluation of Neuroprotective Agents in Transgenic Models of Amyotrophic Lateral Sclerosis. Arch Neurol. 2001;58(8):1315. doi: