Transgenic models of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS), the most frequent paralytic disease of adults, is untreatable and invariably fatal. Up to 20% of ALS cases are inherited (familial, fALS) and associated with mutations, usually of the superoxide dismutase type 1 (SOD-1) gene. This paper shortly reviews the background for and the use of rodent transgenic models of ALS. Silencing the SOD-1 gene does not produce paralytic phenotype, but transgenic rodents expressing human mutated (hm) SOD-1 atop their own enzyme develop relatively selective and fatal degeneration of motoneurons. Many essential neuropathological and biochemical features of the paralytic disease in hmSOD-1 transgenic mice and rats are similar to human fALS, and these animals are currently considered a model of the human disease. Two types of hypotheses put forward to explain pathomechanism of motoneuron degeneration in hmSOD-1 transgenics (hence also in human ALS) are the "gain of function" hypotheses which assume that the mutated enzyme displays new toxic catalytic properties, and the "gain of interaction" hypotheses which assume that the mutated protein molecules are toxic because they became misfolded and undergo oligomerization. Transgenic animal models of ALS are used for preclinical assessments of new therapeutic approaches ranging from mono- and polipharmacotherapy to gene therapy and stem cell therapy.