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

Fragment C of tetanus toxin, more than a carrier. Novel perspectives in non-viral ALS gene therapy.
Fragment C of tetanus toxin, more than a carrier. Novel perspectives in non-viral ALS gene therapy.
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.
1107-3756
297-308
Moreno-Igoa, María
335bc20a-91d8-4b07-aa94-881f7a8908b2
Calvo, Ana Cristina
5dac5232-f924-4fda-ab42-dafb71b74e7e
Penas, Clara
650c6d8e-5990-4765-9a66-2b43fbfe46a1
Manzano, Raquel
32c51040-8d7f-44d0-9dfd-b505b03fbaf5
Oliván, Sara
c79177db-486c-40cf-af50-9ace055241d0
Muñoz, María Jesús
74cd0411-9803-4695-ba21-d3a46b24ff3a
Mancuso, Renzo
4ac1e5c6-f960-4b7d-a718-fd9f5d6be5ea
Zaragoza, Pilar
c6176a36-77df-48e6-9a59-dad9c9a9932e
Aguilera, José
46ce90f8-cef5-4000-8659-fc0c0f81556c
Navarro, Xavier
8854ebaa-d283-4d46-829e-c7c8f186585e
Osta Pinzolas, Rosario
5ef63e8a-6bad-4041-bfe4-04d34ffab203
Moreno-Igoa, María
335bc20a-91d8-4b07-aa94-881f7a8908b2
Calvo, Ana Cristina
5dac5232-f924-4fda-ab42-dafb71b74e7e
Penas, Clara
650c6d8e-5990-4765-9a66-2b43fbfe46a1
Manzano, Raquel
32c51040-8d7f-44d0-9dfd-b505b03fbaf5
Oliván, Sara
c79177db-486c-40cf-af50-9ace055241d0
Muñoz, María Jesús
74cd0411-9803-4695-ba21-d3a46b24ff3a
Mancuso, Renzo
4ac1e5c6-f960-4b7d-a718-fd9f5d6be5ea
Zaragoza, Pilar
c6176a36-77df-48e6-9a59-dad9c9a9932e
Aguilera, José
46ce90f8-cef5-4000-8659-fc0c0f81556c
Navarro, Xavier
8854ebaa-d283-4d46-829e-c7c8f186585e
Osta Pinzolas, Rosario
5ef63e8a-6bad-4041-bfe4-04d34ffab203

Moreno-Igoa, María, Calvo, Ana Cristina, Penas, Clara, Manzano, Raquel, Oliván, Sara, Muñoz, María Jesús, Mancuso, Renzo, Zaragoza, Pilar, Aguilera, José, Navarro, Xavier and Osta Pinzolas, Rosario (2010) Fragment C of tetanus toxin, more than a carrier. Novel perspectives in non-viral ALS gene therapy. International Journal of Molecular Medicine, 88 (3), 297-308. (doi:10.1007/s00109-009-0556-y). (PMID:19921501)

Record type: Article

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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Accepted/In Press date: 13 October 2009
Published date: March 2010
Organisations: Centre for Biological Sciences

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Local EPrints ID: 376119
URI: http://eprints.soton.ac.uk/id/eprint/376119
ISSN: 1107-3756
PURE UUID: 888a53e0-4f2b-498a-af93-1bfc2429fd16

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Date deposited: 24 Apr 2015 11:11
Last modified: 15 Jul 2019 21:23

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Contributors

Author: María Moreno-Igoa
Author: Ana Cristina Calvo
Author: Clara Penas
Author: Raquel Manzano
Author: Sara Oliván
Author: María Jesús Muñoz
Author: Renzo Mancuso
Author: Pilar Zaragoza
Author: José Aguilera
Author: Xavier Navarro
Author: Rosario Osta Pinzolas

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