Amyotrophic Lateral Sclerosis: From Research to Therapeutic Attempts and Therapeutic Perspectives

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive degeneration of motor neurons which brings to muscular atrophy, paralysis and death in 3-5 years from starting symptoms. In about 10% of cases ALS is familiar and in a relevant percent of these cases, mutations of the enzyme copper-zinc superoxide dismutase 1 (SOD1) are found. Transgenic mice expressing mutated forms of SOD1 replicate with fidelity the onset and progression of the disease and have been largely used to test therapies to be translated to patients in clinical trials. Over years, many therapeutic approaches have been attempted in mice model often with significant, albeit limited, benefits on disease onset, progression and lifespan. Unfortunately almost all the clinical trials based on these preclinical results, have been unsuccessful. In the present review, both results of preclinical and clinical studies are summarized, focusing on the main mechanisms that are believed to contribute to this complex disease: oxidative stress, excitotoxicity, neuroinflammation, mitochondrial dysfunction, errors in protein folding and disposal, lack of trophic factors. Future perspectives related to genetic and stem cell approaches are briefly considered.