Physiopathology of ALS: from oxidative stress to RNA metabolism

ALS is a progressive, degenerative disease characterized by selective death of motoneurons in brain and spinal cord. ALS is the most common motoneuron disease that in Sardinia affects 21 people per 100,000 inhabitants. Different ALS causative genes, including SOD1, FUS and TDP43 have been identified in both familial and sporadic ALS cases, suggesting a possible role of these proteins in both forms of the disease. Hypotheses on biology underlying both sporadic and familiar ALS outline a model in which non-competing mechanisms converge in various unsuccessful patterns to mediate motoneuron death. These progresses in understanding the pathological mechanisms in ALS have not been matched with an effective pharmacotherapy.High−throughput experimental strategies (HTS) may provide a potent tool to identify new active drugs for ALS treatment able to interfere with the first cellular alterations, prior to the motoneuronal death. We tested several cellular models where specific markers of cell toxicity, induced by expression of ALS causative genes, may be used as a read-out for HT screening of compound libraries of different nature and we identified roGFP as a good candidate to monitor oxidative stress induced by SOD1.Moreover we got some insight into the pathological mechanism of the Sardinian mutation of TDP43. This pathological mutant promotes cytoplasmic aggregates formations, which do not seem to be causally linked to cell death even if they are considered pathological hallmarks.