GLIAL IMPLICATION IN ALS PATHOGENESIS: TESTING TWO INNOVATIVE THERAPEUTIC APPROACHES

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder that affects about 5 per 100.000 individuals. Its main feature is the progressive loss of muscular function till paralysis. These symptoms are a consequence of the loss of spinal and cerebral motor neurons, the cells deputed to transmit signals from brain to muscles. While the causes of ALS are mainly unknown, about 10% of patients show an inherited form of the disease. Among these familial cases, 20% have been related to mutations of the antioxidant enzyme superoxide dismutase 1 (mtSOD1). This observation has allowed the generation of several experimental models of the disease including transgenic mice that express mtSOD1 and therefore develop a pathology similar to the human disease. This achievement has permitted several mechanistic studies as well as testing of different therapies. Recent investigations performed on these animals showed that motor neurons could not be the exclusive target of mtSOD1 toxicity but the mutant proteins could also affect neighbouring cells, such as astrocytes, which are deputed to the maintenance of the optimal environment for neurons. Since several years, our research group has been engaged in studying the properties of astrocytes in physiological and in pathological conditions. Recently, we have discovered that mtSOD1s themselves are not harmful to astrocytes in culture, but make them sensitive to stimuli normally non-toxic. On the basis of these findings, we propose studies aiming at identifying new drugs potentially candidates for human therapy between two novel classes of therapeutics specifically targeting the events de-regulated in astrocytes during the progression of ALS.