Résumé :
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Here we report an in vitro model system to study the molecular and cellular mechanisms that underlie the neurodegenerative disease Amyotrophic Lateral Sclerosis (ALS). Embryonic stem (ES) cells derived from mice carrying transgenic alleles of the normal or mutant human SOD1 gene were used to generate motor neurons by in vitro differentiation. These motor neurons could be maintained in long-term co-culture with other cells derived from ES cells or with primary glial cells. When co-cultured with SOD1G93A glial cells, mouse motor neurons carrying either the normal human SOD1 transgene or a mutant SOD1G93A allele displayed neurodegenerative properties (SOD1 aggregation, ubiquitin inclusion). Thus, our studies demonstrate that glial cells carrying a human SOD1 mutation have a direct, non cell-autonomous affect on motor neuron survival. More generally, our results demonstrate that ES cell based models of disease can provide a powerful tool for studying the mechanisms of neural degeneration. Moreover, the phenotypes displayed in culture could provide cell-based assays for the identification of new ALS drugs. Currently, we are using human embryonic stem cell-derived motor neurons for further investigate the non-cell autonomous effect of glia cells in ALS.
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