The development of transgenic mouse models of neurodegenerative diseases has been a major advance for testing experimental therapeutics. Transgenic mouse models of amyotrophic lateral sclerosis (ALS) have been produced by overexpressing mutations in the enzyme copper-zinc superoxide dismutase. These mutations are associated with autosomal dominantly inherited ALS. Transgenic mouse models of Huntington disease (HD) have been produced by expressing various-sized fragments of huntingtin with expanded numbers of CAG repeats. The initial diseased model produced was that of Bates and colleagues in which 130 to 140 CAG repeats were expressed in an N-terminal 91–amino acid fragment of huntingtin. Subsequently, mice were produced with a 171–amino acid fragment. We tested a number of potential therapies in both transgenic ALS mice and transgenic HD mice. We monitored the animals' motor performance by means of a rotar, monitored weight loss, and examined survival curves. We also quantified loss of motoneurons in the spinal cord in the ALS mice and quantified striatal degeneration, neuronal size, and numbers of intranuclear neuronal inclusions in the HD mice. In transgenic ALS mice, we found that oral administration of creatine extends survival and reduces the neuropathologic consequences of the disease model in a dose-dependent manner. We found modest protection by trientine, ginkgo biloba, and lipoic acid. We did not see any benefit from administration of desmethylselegiline. In the HD mice, we found significant improvement with oral administration of creatine in 2 transgenic mouse models. This not only extended survival but also significantly attenuated the neuropathologic findings. We also found significant improvement with dichloracetate and with the neuronal nitric oxide synthase inhibitor 7-nitroindazole. These studies, therefore, show the feasibility of carrying out experimental therapeutics in transgenic mouse models of human neurodegenerative diseases.
Beal MF. Huntington Disease. Arch Neurol. 2001;58(8):1315. doi: