A cell culture model to investigate the role of microglia in amyotrophic lateral sclerosis (als)

Despite the selectivity of motoneuron damage in amyotrophic lateral sclerosis (ALS), increasing evidence indicates a participation of microglial cells to motoneuron degeneration in human and murine ALS. Microglia are the resident immune−competent cells of the CNS; notious stimulus may elicit microglia activation and release of toxic factors that accelerate neuronal degeneration and death. However, it is unknown how microglia communicates damage to motoneurons. To unravel the contribution of microglial cells to the pathogenesis of ALS, we are testing the hypothesis of altered pathways of secretion induced by ALS linked mutant superoxide dismutase (mtSOD1) expression in microglia. To this purpose we have recently established cell culture models consisting in human microglial N9 cell lines stably transfected with wild type or G93ASOD1. Our data indicate that the expression of mutant SOD1 increases the release of potentially toxic molecules including mtSOD1, whereas the expression of even higher amount of wt SOD1 does not change the pattern of secretion in N9 microglial cells. Moreover, we have also data suggesting that mt SOD1 is released via unconventional pathways not involving the endoplasmic reticulum-Golgi complex route. We are now performing experiments aimed at identifying the secretory pathway of mutant SOD1, which is a crucial step in order to develop appropriate therapeutic strategies to prevent microglial toxicity.