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.
| Original language | English |
|---|---|
| Pages (from-to) | 81-92 |
| Number of pages | 12 |
| Journal | Annals of Neurology |
| Volume | 62 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Jul 2007 |
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ASJC Scopus subject areas
- Neuroscience(all)
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Fas small interfering RNA reduces motoneuron death in amyotrophic lateral sclerosis mice. / Locatelli, Federica; Corti, Stefania; Papadimitriou, Dimitra; Fortunato, Francesco; Del Bo, Roberto; Donadoni, Chiara; Nizzardo, Monica; Nardini, Martina; Salani, Sabrina; Ghezzi, Serena; Strazzer, Sandra; Bresolin, Nereo; Comi, Giacomo Pietro.
In: Annals of Neurology, Vol. 62, No. 1, 07.2007, p. 81-92.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Fas small interfering RNA reduces motoneuron death in amyotrophic lateral sclerosis mice
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 - 2007/7
Y1 - 2007/7
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=34547764229&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34547764229&partnerID=8YFLogxK
U2 - 10.1002/ana.21152
DO - 10.1002/ana.21152
M3 - Article
C2 - 17503505
AN - SCOPUS:34547764229
VL - 62
SP - 81
EP - 92
JO - Annals of Neurology
JF - Annals of Neurology
SN - 0364-5134
IS - 1
ER -