Antiapoptotic activity maintenance of Brain Derived Neurotrophic Factor and the C fragment of the tetanus toxin genetic fusion protein

Ciriza, Jesús; García‐Ojeda, Marcos E.; Martín-Burriel, Inmaculada; Agulhon, Cendra; Miana-Mena, Francisco Javier; Muñoz, Marı́a Jesús; Zaragoza, Pilar; Brûlet, Philippe; Osta, Rosario

doi:10.2478/s11535-008-0011-z

Cited by 6 publications

(10 citation statements)

References 42 publications

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“…These results are in accordance with the well-known potential of BDNF to enhance the survival of motoneurons in culture and in in vivo models of degeneration [39], presumably through the activation of anti-apoptotic signals, and with the neuroprotective effects of TTC demonstrated in vitro and in vivo , including the prevention of the stress-induced death of cultured neurons and the activation of survival signaling pathways [9,10,15,40]. Interestingly, BDNF-TTC-treated animals showed a similar protein expression pattern to TTC-treated animals, especially of active caspase-3 levels.…”

Section: Discussionsupporting

confidence: 87%

“…We have also observed that TTC and the recombinant fusion protein BDNF-TTC inhibit apoptosis in cultured neurons, with the quimeric molecule being more effective than TTC alone [9]. BDNF may cause a relocalization of membrane domains containing TTC receptors by activating Trk receptors, thereby facilitating the neuronal internalization of TTC.…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, recent evidence has raised the potential use of the TTC heavy chain as a therapeutic agent for neurodegeneration. In vitro studies have reported that TTC rescues degenerating cultured neurons from apoptotic death through the activation of phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) survival signaling pathways [ 9 ]. Furthermore, our group has recently described that the intramuscular gene delivery of TTC in SOD1 G93A mice exerts a positive effect on the prevention of neurodegeneration, improves motor function, inhibits apoptotic pathways and prolongs the survival of these animals [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

“…A previous study reported that some neurotrophic factors, in particular brain derived neurotrophic factor (BDNF), facilitate the internalization of TTC fusion molecules in motor nerve terminals [ 14 ]. We have also observed that TTC and the recombinant fusion protein BDNF-TTC inhibit apoptosis in cultured neurons, with the quimeric molecule being more effective than TTC alone [ 9 ]. BDNF may cause a relocalization of membrane domains containing TTC receptors by activating Trk receptors, thereby facilitating the neuronal internalization of TTC.…”

Section: Introductionmentioning

confidence: 99%

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Lack of a synergistic effect of a non-viral ALS gene therapy based on BDNF and a TTC fusion molecule

Calvo

Moreno-Igoa

Mancuso

et al. 2011

Orphanet J Rare Dis

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BackgroundAmyotrophic lateral sclerosis (ALS) is one of the most devastating neurodegenerative diseases. Neurotrophic factors have been widely tested to counteract neurodegenerative conditions, despite their unspecific neuronal access. The non-toxic C-terminal fragment of the tetanus toxin (TTC) heavy chain has been studied not only as a carrier molecule to the CNS but also as a neuroprotective agent. Because the neurotrophic effects of BDNF have been demonstrated in vitro and in vivo, the question addressed in this work is whether a fusion molecule of BDNF-TTC may have a synergistic effect and enhance the neuroprotective properties of TTC alone in a mouse model of ALS.MethodsRecombinant plasmid constructs (pCMV-TTC and pCMV-BDNF-TTC) were injected into the quadriceps femoris and triceps brachialis muscles of SOD1G93A transgenic mice at 8 weeks of age. The hanging wire and rotarod tests were performed to assess motor coordination, strength and balance. Electrophysiological tests, morphological assays of spinal cord sections of L2 and L4 segments, and gene and protein expression analyses were performed. The Kaplan-Meier survival analysis test was used for comparisons of survival. Multiple comparisons of data were analyzed using a one-way analysis of variance (ANOVA).ResultsTreatment with the fusion-molecule BDNF-TTC and with TTC alone significantly delayed the onset of symptoms and functional deficits of SOD1G93A mice. Muscle innervation was partially preserved with these treatments, and the number of surviving motoneurons in L2 spinal cord segment was increased particularly by the fusion protein induction. Inhibition of pro-apoptotic protein targets (caspase-3 and Bax) and significant phosphorylation of Akt and ERK were also found in the spinal cord of treated mice.ConclusionsSignificant improvements in behavioral and electrophysiological results, motoneuron survival and anti-apoptotic/survival-activated pathways were observed with BDNF-TTC treatment. However, no synergistic effect was found for this fusion molecule. Although BDNF in the fusion molecule is capable of activating autocrine and neuroprotective pathways, TTC treatment alone yielded similar neuroprotection. Therefore, an accurate study of the neuroprotective effects of TTC fusion molecules should be performed to obtain a better understanding of its effects.

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Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Lack of a synergistic effect of a non-viral ALS gene therapy based on BDNF and a TTC fusion molecule

Calvo

Moreno-Igoa

Mancuso

et al. 2011

Orphanet J Rare Dis

Self Cite

View full text Add to dashboard Cite

show abstract

“…A previous study reported that some neurotrophic factors, in particular BDNF, facilitate the internalization of TTC recombinant molecules in motor nerve terminals [69]. In addition, TTC and the recombinant protein BDNF-TTC can inhibit apoptosis in cultured neurons, with the quimeric molecule being more effective than TTC alone [70]. Interestingly, BDNF may cause a relocalization of membrane domains containing TTC receptors by activating Trk receptors, thereby facilitating the neuronal internalization of TTC.…”

Section: Neuroprotective Properties Of Recombinant Molecules Of Ttc Imentioning

confidence: 99%

Gene Therapy Based on Fragment C of Tetanus Toxin in ALS: A Promising Neuroprotective Strategy for the Bench to the Bedside Approach

Calvo¹,

Zaragoza²,

Osta³

2013

Gene Therapy - Tools and Potential Applications

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Therapeutic Assay with the Non-toxic C-Terminal Fragment of Tetanus Toxin (TTC) in Transgenic Murine Models of Prion Disease

et al. 2021

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The non-toxic C-terminal fragment of the tetanus toxin (TTC) has been described as a neuroprotective molecule since it binds to Trk receptors and activates Trk-dependent signaling, activating neuronal survival pathways and inhibiting apoptosis. Previous in vivo studies have demonstrated the ability of this molecule to increase mice survival, inhibit apoptosis and regulate autophagy in murine models of neurodegenerative diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy. Prion diseases are fatal neurodegenerative disorders in which the main pathogenic event is the conversion of the cellular prion protein (PrPC) into an abnormal and misfolded isoform known as PrPSc. These diseases share different pathological features with other neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson’s disease or Alzheimer’s disease. Hitherto, there are no effective therapies to treat prion diseases. Here, we present a pilot study to test the therapeutic potential of TTC to treat prion diseases. C57BL6 wild-type mice and the transgenic mice Tg338, which overexpress PrPC, were intracerebrally inoculated with scrapie prions and then subjected to a treatment consisting of repeated intramuscular injections of TTC. Our results indicate that TTC displays neuroprotective effects in the murine models of prion disease reducing apoptosis, regulating autophagy and therefore increasing neuronal survival, although TTC did not increase survival time in these models.

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Antiapoptotic activity maintenance of Brain Derived Neurotrophic Factor and the C fragment of the tetanus toxin genetic fusion protein

Cited by 6 publications

References 42 publications

Lack of a synergistic effect of a non-viral ALS gene therapy based on BDNF and a TTC fusion molecule

Lack of a synergistic effect of a non-viral ALS gene therapy based on BDNF and a TTC fusion molecule

Gene Therapy Based on Fragment C of Tetanus Toxin in ALS: A Promising Neuroprotective Strategy for the Bench to the Bedside Approach

Therapeutic Assay with the Non-toxic C-Terminal Fragment of Tetanus Toxin (TTC) in Transgenic Murine Models of Prion Disease

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