Experimental models for the study of neurodegeneration in amyotrophic lateral sclerosis

Abstract

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of unknown cause, characterized by the selective and progressive death of both upper and lower motoneurons, leading to a progressive paralysis. Experimental animal models of the disease may provide knowledge of the pathophysiological mechanisms and allow the design and testing of therapeutic strategies, provided that they mimic as close as possible the symptoms and temporal progression of the human disease. The principal hypotheses proposed to explain the mechanisms of motoneuron degeneration have been studied mostly in models in vitro, such as primary cultures of fetal motoneurons, organotypic cultures of spinal cord sections from postnatal rodents and the motoneuron-like hybridoma cell line NSC-34. However, these models are flawed in the sense that they do not allow a direct correlation between motoneuron death and its physical consequences like paralysis. In vivo, the most widely used model is the transgenic mouse that bears a human mutant superoxide dismutase 1, the only known cause of ALS. The major disadvantage of this model is that it represents about 2%–3% of human ALS. In addition, there is a growing concern on the accuracy of these transgenic models and the extrapolations of the findings made in these animals to the clinics. Models of spontaneous motoneuron disease, like the wobbler and pmn mice, have been used aiming to understand the basic cellular mechanisms of motoneuron diseases, but these abnormalities are probably different from those occurring in ALS. Therefore, the design and testing of in vivo models of sporadic ALS, which accounts for >90% of the disease, is necessary. The main models of this type are based on the excitotoxic death of spinal motoneurons and might be useful even when there is no definitive demonstration that excitotoxicity is a cause of human ALS. Despite their difficulties, these models offer the best possibility to establish valid correlations between cellular alterations and motor behavior, although improvements are still necessary in order to produce a reliable and integrative model that accurately reproduces the cellular mechanisms of motoneuron degeneration in ALS.