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

Authors

  • Federica Locatelli MD,

    1. Dino Ferrari Centre, Department of Neurological Sciences, University of Milan, IRCCS Foundation Ospedale Maggiore Policlinico Mangiagalli and Regina Elena, Milan, Italy
    2. IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy
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    • F.L. and S.C. contributed equally to this work.

  • Stefania Corti MD,

    1. Dino Ferrari Centre, Department of Neurological Sciences, University of Milan, IRCCS Foundation Ospedale Maggiore Policlinico Mangiagalli and Regina Elena, Milan, Italy
    2. Centre of Excellence on Neurodegenerative Diseases, University of Milan, Milan, Italy
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    • F.L. and S.C. contributed equally to this work.

  • Dimitra Papadimitriou MD,

    1. Dino Ferrari Centre, Department of Neurological Sciences, University of Milan, IRCCS Foundation Ospedale Maggiore Policlinico Mangiagalli and Regina Elena, Milan, Italy
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  • Francesco Fortunato BS,

    1. Dino Ferrari Centre, Department of Neurological Sciences, University of Milan, IRCCS Foundation Ospedale Maggiore Policlinico Mangiagalli and Regina Elena, Milan, Italy
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  • Roberto Del Bo PhD,

    1. Dino Ferrari Centre, Department of Neurological Sciences, University of Milan, IRCCS Foundation Ospedale Maggiore Policlinico Mangiagalli and Regina Elena, Milan, Italy
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  • Chiara Donadoni PhD,

    1. Dino Ferrari Centre, Department of Neurological Sciences, University of Milan, IRCCS Foundation Ospedale Maggiore Policlinico Mangiagalli and Regina Elena, Milan, Italy
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  • Monica Nizzardo PhD,

    1. Dino Ferrari Centre, Department of Neurological Sciences, University of Milan, IRCCS Foundation Ospedale Maggiore Policlinico Mangiagalli and Regina Elena, Milan, Italy
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  • Martina Nardini PhD,

    1. Dino Ferrari Centre, Department of Neurological Sciences, University of Milan, IRCCS Foundation Ospedale Maggiore Policlinico Mangiagalli and Regina Elena, Milan, Italy
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  • Sabrina Salani PhD,

    1. Dino Ferrari Centre, Department of Neurological Sciences, University of Milan, IRCCS Foundation Ospedale Maggiore Policlinico Mangiagalli and Regina Elena, Milan, Italy
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  • Serena Ghezzi PhD,

    1. Dino Ferrari Centre, Department of Neurological Sciences, University of Milan, IRCCS Foundation Ospedale Maggiore Policlinico Mangiagalli and Regina Elena, Milan, Italy
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  • Sandra Strazzer MD,

    1. IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy
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  • Nereo Bresolin MD,

    1. Dino Ferrari Centre, Department of Neurological Sciences, University of Milan, IRCCS Foundation Ospedale Maggiore Policlinico Mangiagalli and Regina Elena, Milan, Italy
    2. IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy
    3. Centre of Excellence on Neurodegenerative Diseases, University of Milan, Milan, Italy
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  • Giacomo Pietro Comi MD

    Corresponding author
    1. Dino Ferrari Centre, Department of Neurological Sciences, University of Milan, IRCCS Foundation Ospedale Maggiore Policlinico Mangiagalli and Regina Elena, Milan, Italy
    2. Centre of Excellence on Neurodegenerative Diseases, University of Milan, Milan, Italy
    • 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
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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

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