Fas small interfering RNA reduces motoneuron death in amyotrophic lateral sclerosis mice.

@article{citeulike:1304671, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease characterized by selective motoneuron death. Understanding of the molecular mechanisms that trigger and regulate motoneuron degeneration could be relevant to ALS and other motoneuron disorders. This study investigates the role of Fas-linked motoneuron death in the pathogenesis of ALS. METHODS: We performed in vitro and in vivo small interfering RNA-mediated interference, by silencing the Fas receptor on motoneurons that carry the superoxide dismutase-1 (SOD1)-G93A mutation. RESULTS: We observed a significant reduction in Fas expression at messenger RNA (p < 0.001) and protein levels. Treated motoneurons demonstrated an increase in survival and a reduction in cytochrome c release from mitochondria. In vivo, continuous intrathecal administration of Fas small interfering RNA by an osmotic minipump improved motor function and survival in SOD1-G93A mice (mean increase, 18 days; p < 0.0001). Treated mice showed a significant reduction in Fas and Fas mediators p38 mitogen-activated protein kinase, neuronal nitric oxide synthase, and caspase-8. INTERPRETATION: Fas silencing interferes with motoneuron-specific downstream death pathways and results in increased motoneuron survival and amelioration of the SOD1-G93A phenotype, suggesting new possible strategies for molecular therapy of ALS. Ann Neurol 2007.}, address = {Dino Ferrari Centre, Department of Neurological Sciences, University of Milan, IRCCS Foundation Ospedale Maggiore Policlinico Mangiagalli and Regina Elena, Milan, Italy.}, author = {Locatelli, Federica and Corti, Stefania and Papadimitriou, Dimitra and Fortunato, Francesco and Del Bo, Roberto and Donadoni, Chiara and Nizzardo, Monica and Nardini, Martina and Salani, Sabrina and Ghezzi, Serena and Strazzer, Sandra and Bresolin, Nereo and Comi, Giacomo Pietro P. }, citeulike-article-id = {1304671}, doi = {http://dx.doi.org/10.1002/ana.21152}, issn = {0364-5134}, journal = {Ann Neurol}, keywords = {rnai, sirna}, month = {May}, posted-at = {2007-05-18 04:54:32}, priority = {2}, title = {Fas small interfering RNA reduces motoneuron death in amyotrophic lateral sclerosis mice.}, url = {http://dx.doi.org/10.1002/ana.21152}, year = {2007} }

TY - JOUR ID - citeulike:1304671 L3 - citeulike-article-id:1304671 TI - Fas small interfering RNA reduces motoneuron death in amyotrophic lateral sclerosis mice. JF - Ann Neurol AD - Dino Ferrari Centre, Department of Neurological Sciences, University of Milan, IRCCS Foundation Ospedale Maggiore Policlinico Mangiagalli and Regina Elena, Milan, Italy. SN - 0364-5134 N2 - OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease characterized by selective motoneuron death. Understanding of the molecular mechanisms that trigger and regulate motoneuron degeneration could be relevant to ALS and other motoneuron disorders. This study investigates the role of Fas-linked motoneuron death in the pathogenesis of ALS. METHODS: We performed in vitro and in vivo small interfering RNA-mediated interference, by silencing the Fas receptor on motoneurons that carry the superoxide dismutase-1 (SOD1)-G93A mutation. RESULTS: We observed a significant reduction in Fas expression at messenger RNA (p < 0.001) and protein levels. Treated motoneurons demonstrated an increase in survival and a reduction in cytochrome c release from mitochondria. In vivo, continuous intrathecal administration of Fas small interfering RNA by an osmotic minipump improved motor function and survival in SOD1-G93A mice (mean increase, 18 days; p < 0.0001). Treated mice showed a significant reduction in Fas and Fas mediators p38 mitogen-activated protein kinase, neuronal nitric oxide synthase, and caspase-8. INTERPRETATION: Fas silencing interferes with motoneuron-specific downstream death pathways and results in increased motoneuron survival and amelioration of the SOD1-G93A phenotype, suggesting new possible strategies for molecular therapy of ALS. Ann Neurol 2007. KW - rnai KW - sirna AU - Locatelli, Federica AU - Corti, Stefania AU - Papadimitriou, Dimitra AU - Fortunato, Francesco AU - Del Bo, Roberto AU - Donadoni, Chiara AU - Nizzardo, Monica AU - Nardini, Martina AU - Salani, Sabrina AU - Ghezzi, Serena AU - Strazzer, Sandra AU - Bresolin, Nereo AU - Comi, Giacomo Pietro PY - 2007/05/14/ UR - http://dx.doi.org/10.1002/ana.21152 ER -