Affiliations: Laboratorio de Genética Bioquímica, Facultad de Veterinaria, Universidad de Zaragoza, Zaragoza, Spain | School of Natural Sciences, University of California, Merced, CA, USA
Note: [] Corresponding author: Rosario Osta, Laboratorio de Genética Bioquímica (LAGENBIO-I3A), Facultad de Veterinaria, Universidad de Zaragoza, C/Miguel Servet, 177, 50013 Zaragoza, Spain. Tel.: +34976761621; Fax: +34976761612; E-mail: [email protected]
Abstract: Purpose and background: Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease with no effective therapy. Glial-cell line derived neurotrophic factor (GDNF) has been translated to clinical trials for treatment of ALS and its selective delivery to the motoneurons could improve its therapeutic abilities. Methods: To test this idea, we genetically fused GDNF to the C-fragment of tetanus toxin (TTC), a peptide able to specifically deliver molecules to motoneurons. Results: Single intramuscular administration of naked-DNA encoding GDNF or GDNF-TTC significantly delayed the onset of symptoms and functional deficits into the SODG93A mouse model of ALS, prolonging their lifespan. Conclusions: We have demonstrated a neuroprotective effect of GDNF-TTC as shown by the activation of survival pathways and inhibition of apoptotic proteins, such as Akt phosphorylation, or reduced caspase-3 activation respectively. However, the GDNF fusion with TTC did not improve the therapeutic effects when compared to GDNF alone.
Keywords: Amyotrophic lateral sclerosis (ALS), Glial-cell line derived neurotrophic factor (GDNF), C-fragment tetanus toxin (TTC), neuronal apoptosis, SODG93A mouse model
