Autores: Mauro Agrò. Directores de la Tesis: Javier DÃaz Nido (dir. tes.), Alfredo Giménez-Cassina Sendón (codir. tes.). Lectura: En la Universidad Autónoma de Madrid ( España ) en 2019. Idioma: español.
The regulation of frataxin gene expression is another issue of major interest for its possible therapeutic relevance. Several factors including Erythropoietin and some Epo-mimetic molecules have been reported to increase frataxin levels. There are some drawbacks, since canonical Epo can cause hematocrit problems, while some of the derivative peptides described are known to be highly unstable, with a very low half-life in the organism. For this reason, we decided to focus on a retro-enantiomeric version of a HBSP-based peptide, called EPO2. We described in this work the positive regulatory effects on frataxin of this synthetic epomimetic peptide, both in vitro in several cell models and in vivo in the cerebellum of wild type mice.
Finally, we reported the effects of spontaneous physical activity in wild type mouse cerebellum on frataxin expression. Frataxin levels appeared positively modulated after exercise, suggesting a post-transcriptional regulation mechanism. We investigated for possible mediators of this beneficial effect by qPCRs and through a cytokine array which highlighted the upregulation of several factors, including the neurotrophin NT-3, SHH protein, MIP-1α and IFN-γ, pointing the way to a multi-layered regulatory complex behind frataxin modulation set up by physical exercise.
