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Fragment C of tetanus toxin, more than a carrier. Novel perspectives in non-viral ALS gene therapy

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Abstract

The non-toxic carboxy-terminal fragment of tetanus toxin heavy chain (TTC) has been implicated in the activation of cascades responsible for trophic actions and neuroprotection by inhibition of apoptosis. Previous in vitro studies have described signalling pathways that underlie the administration of TTC to neurons. We investigated whether these properties were maintained in a mouse model of neurodegenerative disease. Naked DNA encoding for TTC was injected intramuscularly and neuromuscular function and clinical behaviour were monitored until endstage in the transgenic SOD1G93A mouse model that expresses a mutant variant of human superoxide dismutase 1 (SOD1). Our results indicate that TTC treatment ameliorated the decline of hindlimb muscle innervation, significantly delayed the onset of symptoms and functional deficits, improved spinal motor neuron survival, and prolonged lifespan. Furthermore, we found that caspase-1 and caspase-3 proapoptotic genes were down-regulated in the spinal cord of treated mice. Western blot analysis showed that the active form of caspase-3 was also down-regulated after TTC treatment and survival signals, such as the significant phosphorylation of serine/threonine protein kinase Akt, were also detected. These results suggest that fragment C of tetanus toxin, TTC, provides a potential therapy for neurodegenerative diseases.

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Acknowledgments

We wish to thank David Rodriguez and Jesus Navarro for their technical support. We also thank Jessica Jaramillo for histological processing. This work was supported by grants PI071133 and PI060201, CIBERNED and TERCEL funds from the Fondo de Investigación Sanitaria of Spain, SAF2006-15184 from the Ministerio de Educación y Ciencia of Spain, FEDER, Action COST-B30 of the EC, the Government of Navarra and the Project “Tú eliges: tú decides” of Caja de Ahorros de Navarra in Spain.

Conflict of interest statement

All our affiliations, corporate or institutional, and all sources of financial support for this research are properly acknowledged. We certify that we do not have any commercial or associate interests that represent a conflict of interest in connection with this manuscript.

Ethical statement

All experimental procedures were approved by the Ethics Committees of our institutions and followed the international guidelines for the use of laboratory animals based on the guidelines for the preclinical in vivo evaluation of pharmacological active drugs for ALS/MND (Report on the 142nd ENMC international workshop for the establishment of guidelines for the conduct of preclinical and proof of concept studies in ALS/MND models, published in Amyotroph Lateral Scler 8: 217-223, 2007).

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Authors and Affiliations

  1. LAGENBIO-I3A, Aragon’s Institute of Health Sciences (IACS), University of Zaragoza, Miguel Servet, 177. 50013, Zaragoza, Spain

    María Moreno-Igoa, Ana Cristina Calvo, Raquel Manzano, Sara Oliván, María Jesús Muñoz, Pilar Zaragoza & Rosario Osta Pinzolas

  2. Department of Cell Biology, CIBERNED Group of Neuroplasticity and Regeneration, Institute of Neurosciences, Physiology and Immunology, Universitat Autònoma de Barcelona, 08193, Cerdanyola del Vallès, Spain

    Clara Penas, Renzo Mancuso & Xavier Navarro

  3. Department of Biochemistry and Molecular Biology, Institute of Neurosciences, Universitat Autònoma de Barcelona, 08193, Cerdanyola del Vallès, Spain

    José Aguilera

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  1. María Moreno-Igoa
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  2. Ana Cristina Calvo
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Correspondence to Rosario Osta Pinzolas.

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María Moreno-Igoa and Ana Cristina Calvo contributed equally to this work (as first authors).

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Moreno-Igoa, M., Calvo, A.C., Penas, C. et al. Fragment C of tetanus toxin, more than a carrier. Novel perspectives in non-viral ALS gene therapy. J Mol Med 88, 297–308 (2010). https://doi.org/10.1007/s00109-009-0556-y

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  • DOI: https://doi.org/10.1007/s00109-009-0556-y

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