Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two tightly connected neurodegenerative diseases overlapping in clinical, pathological and genetic features. Mutations in more than 25 genes have been suggested to cause ALS/FTD, including G4C2 hexanucleotide repeat expansions in the C9orf72 gene, which is the most frequent cause of ALS (40% fALS, 7% sALS cases) and FTD (20% familial cases). Pathogenic mechanisms leading to neurodegeneration in these patients are currently unknown but three hypotheses have been proposed: the toxic accumulation of (G4C2)n‑rich RNA transcripts, the non-canonical repeat-associated non-ATG (RAN) translation producing dipeptide polymers prone to aggregation, and finally the loss of function of the C9orf72 protein.
My research is focused in determine the effector pathways leading to neurodegeneration in C9orf72 ALS/FTD by using pure FACS-isolated motor neurons from iPSC from C9orf72 patients. Transcriptomic analysis of these motor neurons and gene overexpression/knock down of the selected effectors will be carried out for this purpose. The identified effectors will be tested as targets for pharmacological therapy in a zebrafish model of G4C2-linked ALS/FTD.
Effect of the C-terminal domain of the heavy chain of tetanus toxin on dyskinesia caused by levodopa in 6-hydroxydopamine-lesioned rats.
Palafox-Sánchez V. et al, (2016), Pharmacol Biochem Behav, 145, 33 - 44
The restorative effect of intramuscular injection of tetanus toxin C-fragment in hemiparkinsonian rats.
Sánchez-González A. et al, (2014), Neurosci Res, 84, 1 - 9
Trk receptors need neutral sphingomyelinase activity to promote cell viability.
Candalija A. et al, (2014), FEBS Lett, 588, 167 - 174
Tetanus Toxin Hc Fragment Induces the Formation of Ceramide Platforms and Protects Neuronal Cells against Oxidative Stress.
Cubí R. et al, (2013), PLoS One, 8