APOPTOSIS OF SPINAL CORD ASTROCYTES SECONDARY TO ALS-LINKED SOD1 MUTATIONS: MECHANISM, RELEVANCE FOR MOTOR NEURON DEGENERATION AND PROTECTIVE PHARMACOLOGICAL INTERVENTION

Amyotrophic lateral sclerosis (ALS) is a human neurodegenerative disorder affecting 5 per 100,000 individuals and characterised by a progressive loss of spinal and cerebral motor neurons that leads to muscular weakness and paralysis. Although the causes of ALS are unclear, it has been known for a number of years that at least 10% of ALS patients develop a hereditary form of the disease with a genetic basis. In 20% of these familial cases, the responsible mutated gene has been identified as the one encoding the antioxidant enzyme copper zinc superoxide dismutase, named SOD1. It has also been discovered that mutant SOD1 (mtSOD1) is toxic to motor neurons because it acquires an altered function and not because of a decrease in its antioxidant activity. Recent studies suggest that motor neurons may not be the only or preferential target of mtSOD1. mtSOD1 might also be deleterious for cells surrounding neurons, such as astrocytes, which maintain motor neurons in the ideal microenvironment for their activity and survival. If mtSOD1 affects the functions of astrocytes, then motor neurons will be in an unfavourable microenvironment, which will result in their slow degeneration. Since our research group has a vast expertise in astrocyte properties, we propose studies focusing on the role of astrocytes in motor neuron death by investigating specific alterations, developing drugs blocking the identified defects and finally testing the agents in transgenic mice showing the symptomatology of human ALS.