SOD1-LINKED FAMILIAL AMYOTROPHIC LATERAL SCLEROSIS: NOVEL STRATEGIES TO RESCUE MITOCHONDRIAL DAMAGE IN MOTOR NEURONS

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease caused by the progressive loss of motor neurons and paralysis of the patients, affecting 4-6 people in 100,000. 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. Some authors believe that those mutations cause the appearance of a toxic function in an enzyme that is typically protective and involved in the scavenging of dangerous oxygen radicals. Others 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. Recent evidence indicates that mitochondria, the cell energy factory, are one of the primary location of damage inside motor neurons. Dysfunction of mitochondria is observed early in patients (and in experimental models for ALS) and causes the death of neurons, which underlies onset of paralysis and death of patients. In this project, we propose to attempt rescue of correct mitochondrial function in experimental models for SOD1-linked familial ALS. Up to date no effective therapy exists for fALS and only support treatment is administered to patients, who invariably die a few years after onset of symptoms. Individuation of new strategies to intercept damage due to the action of mutant SOD1 inside mitochondria may allow devising new therapeutic approaches.