SOD1-LINKED FAMILIAL AMYOTROPHIC LATERAL SCLEROSIS: UNDERSTANDING THE TOXIC FUNCTION OF THE MUTANT ENZYMES

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease caused by the progressive loss of motor neurones and paralysis of the patients, affecting 4-6 people in 100000. About one fifth of the patients is affected by the familiar form of the disease (FALS) and 20% of FALS forms are associated with mutations in the gene coding for Cu,Zn superoxide dismutase (SOD1), an enzyme involved in the metabolism of oxygen radicals. The mechanisms by which mutations in the gene sod1 cause onset of disease are still largely unknown. Some Authors believe that those mutations cause the appearance of a toxic, pro-oxidant function in an enzyme that is typically anti-oxidant and involved in the scavenging of dangerous oxygen radicals. Other Researchers hypothesize that mutant enzymes, because of their altered structure, can form intracellular bodies where proteins are abnormally aggregated and that those bodies cause neuronal death. This discrepancy most probably arises from the fact that no thorough study of the intracellular toxic function(s) of mutant SOD1s has ever been performed (more than 90 variants have been described in patients). We propose to attempt a methodical study, on a large number of SOD1 variants, aimed to the unraveling the molecular mechanisms of the toxic function of these proteins; such a function causes the death of neurones, which underlies onset of paralysis and death of patients. Up to date no effective therapy exists for FALS and only palliative treatment is administered. Individuation of cell pathways altered by the obnoxious action of mutant SOD1s may allow devising new therapeutic approaches aimed to interception or removal of toxic molecules.