IN VITRO AND IN VIVO STUDIES ON THE INTERPLAY BETWEEN INFLAMMATORY AND EXCITOTOXIC MECHANISMS AND ON THE ROLE OF P38 MITOGEN ACTIVATED PROTEIN KINASE PATHWAY IN THE PATHOGENESIS OF FAMILIAL AMYOTROPHIC LATERAL SCLEROSIS

Amyotrophic lateral sclerosis (ALS) is the most common disease affecting motor neurons, which leads to a progressive paralysis and death. In about 10% of ALS cases the disease is inherited (familial ALS) and among that one fifth is caused by mutations of the superoxide dismutase 1 (SOD1) gene. To date, the pathogenetic mechanisms of ALS are largely unknown and there are no effective therapies. Among the factors contributing to ALS, an excess of glutamate activity (excitotoxicity) and of pro-inflammatory cytokines (neuroinflammation) have been suggested to play a major role. Recent findings suggest that inflammatory mediators in particular TNFa and its intracellular signalling pathway involving p38MAPK, that are normally expressed in the spinal cord, are upregulated during motor neuron degeneration occurring in ALS. Evidences also suggest that these factors can contribute to the excitotoxic process by altering the expression and activity of glutamate AMPA receptors on neurons, including motor neurons. In this project, we intend to investigate whether the link between TNFa, p38MAPK and AMPA glutamate receptors may play a key role in the triggering of neuronal death in ALS using different experimental paradigms (in vivo and in vitro models) derived from transgenic mice carrying mutant SOD1, a model which recapitulates many aspects of the disease. We will also examine whether the interception at different levels of these converging pathways, using drug treatments or the most alternative but promising approaches such as the gene expression silencing, may have a major impact in preventing the neuronal damage associated to ALS. There are already some drugs available that have been designed to block TNFa and p38MAPK pathways or AMPA glutamate receptors, but it is important to establish if they can be beneficial in animal models when administered alone and in combination.