A NOVEL ANIMAL MODEL FOR AMYOTROPHIC LATERAL SCLEROSIS: THE SOD1G93A TRANSGENIC SWINE.

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that may occur in two clinically indistinguishable forms: sporadic (sALS) and familial (fALS), the latter linked to several gene mutations, mostly inheritable in a dominant fashion [Rosen et al., 1993]. The disease is characterized by selective and progressive degeneration of upper and lower motor neurons, leading to muscle weakness, atrophy and evolving to complete paralysis that results in patient death in 2 to 5 years after symptoms onset. Research on ALS has mainly relied so far on experimental rodent models carrying a variety of Cu/Zn Superoxide Dismutase 1 (SOD1) mutations. Currently, the most widely employed model is a transgenic mouse with a glycine to alanine conversion at the 93rd codon (G93A) of the SOD1 gene. These mice reliably reproduce the ALS patients phenotype progression, developing a rapidly progressive motor neuron degeneration. Death occurs about four months after symptoms onset [Turner & Talbot, 2008], not reflecting the disease course in human patients. Although the use of these murine models is currently widespread both in clinical trials and in basic research, aimed at a resolution of the pathogenic mechanisms underlying the disease, doubts have been recently raised, from numerous reliable sources [Schnabel, 2008; Benatar, 2007; Van Den Bosch, 2011; Gordon et al., 2007] about rodents suitability to faithfully reproduce the human disease. Since human and rodent species differ in life-span, physiology, anatomy and biochemical aspects, data extrapolation has proved to be difficult. As a matter of fact, encouraging results of drug tests in rodents have never been so far successfully translated to humans, and, in some cases, molecules delaying disease progression in transgenic mice, such as minocycline, have resulted even detrimental in ALS patients [Scott et al., 2008] also because of the heterogeneity of mouse genetic background [Schnabel, 2008]. The scientific community has already accepted swine as an attractive model, alternative to non-human primates, for pharmacological and surgical testing as well as for biomedical research on the basis of its anatomical, physiological and biochemical features that are more closely related to human species than the rodent ones. Furthermore, the prospect of obtaining genetically modified pigs further extended their biomedical potential especially to mimic inherited human diseases [Bendixen et al., 2010]. In particular, regarding Central Nervous System (CNS) anatomy, pig brain cortical surface resembles human gyrencephalic neocortex and similarities with the human brain have also been demonstrated for the hippocampus, subcortical and diencephalic nuclei and brainstem structures. Furthermore, pig brain size permits an easy identification of cortical and subcortical structures by conventional imaging techniques and offers invaluable opportunities for microsurgical techniques and intrathecal drugs administration. Consistently, the swine large size and long lifespan allow to perform…