title: Fas small interfering RNA reduces motoneuron death in amyotrophic lateral sclerosis mice.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Dino Ferrari Centre, Department of Neurological Sciences, University of Milan, IRCCS Foundation Ospedale Maggiore Policlinico Mangiagalli and Regina Elena, Padiglione Ponti, Via Francesco Sforza 35, 20122 Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Locatelli
authors.forename: Stefania
authors.initials: S
authors.lastname: Corti
authors.forename: Dimitra
authors.initials: D
authors.lastname: Papadimitriou
authors.forename: Francesco
authors.initials: F
authors.lastname: Fortunato
authors.forename: Roberto
authors.initials: R
authors.lastname: Del Bo
authors.forename: Chiara
authors.initials: C
authors.lastname: Donadoni
authors.forename: Monica
authors.initials: M
authors.lastname: Nizzardo
authors.forename: Martina
authors.initials: M
authors.lastname: Nardini
authors.forename: Sabrina
authors.initials: S
authors.lastname: Salani
authors.forename: Serena
authors.initials: S
authors.lastname: Ghezzi
authors.forename: Sandra
authors.initials: S
authors.lastname: Strazzer
authors.forename: Nereo
authors.initials: N
authors.lastname: Bresolin
authors.forename: Giacomo Pietro
authors.initials: GP
authors.lastname: Comi
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D053222:Fas Ligand Protein / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D034741:RNA, Small Interfering / Q000627:therapeutic use*; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D013116:Spinal Cord / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics; D013997:Time Factors; D014162:Transfection; D019014:fas Receptor / Q000235:genetics*
chemical_list: D053222:Fas Ligand Protein; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D017475:Receptors, Nerve Growth Factor; C517634:Ngfr protein, mouse; D019014:fas Receptor; D049452:Green Fluorescent Proteins; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase