Objetivo Friedreich’s Ataxia (FRDA) is a devastating degenerative disease with no specific therapy. It is passed by autosomal recessive inheritance and affects 1:30,000 individuals in Caucasian populations. Symptoms appear in the first decade of life and include progressive and unremitting lack of movement coordination, leading to complete inability, and dilated cardiomyopathy leading to congestive heart failure, the most common cause of premature death. FRDA is due to the insufficient transcription of the gene coding for the mitochondrial protein frataxin. Reduced cellular levels of frataxin cause impaired mitochondrial function and increased sensitivity to oxidative stress, leading to accelerated cell death in critical tissues.Severity of the disease critically depends on residual frataxin levels. Therapeutic efforts are mostly focused on increasing cellular frataxin . We found that frataxin is normally degraded by the ubiquitin-proteasome system. We identified the lysine responsible for the ubiquitination of frataxin and, by computational screening followed by experimental validation, we identified and validated a series of small molecules, called ubiquitin-competing molecules (UCM), that prevent frataxin ubiquitination and induce frataxin accumulation in cells derived from FRDA patients. Moreover, treatment with UCM partially rescues aconitase and ATP production defects in cells derived from FRDA patients.Our goal is two fold: 1) submit a set of leads we already identified, as well as their new and more complex derivatives, to preclinical testing in FRDA mice 2) identify the E3 ligase that is responsible for frataxin ubiquitination, and investigate the possibility to use it as a druggable target for small molecules to prevent frataxin degradation. Ámbito científico natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsmedical and health sciencesclinical medicinecardiology Programa(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Tema(s) ERC-AG-LS7 - ERC Advanced Grant - Diagnostic tools, therapies and public health Convocatoria de propuestas ERC-2011-ADG_20110310 Consulte otros proyectos de esta convocatoria Régimen de financiación ERC-AG - ERC Advanced Grant Institución de acogida UNIVERSITA DEGLI STUDI DI ROMA TOR VERGATA Aportación de la UE € 1 496 200,00 Dirección VIA CRACOVIA 50 00133 Roma Italia Ver en el mapa Región Centro (IT) Lazio Roma Tipo de actividad Higher or Secondary Education Establishments Investigador principal Roberto Testi (Prof.) Contacto administrativo Giuseppe Novelli (Prof.) Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Coste total Sin datos Beneficiarios (1) Ordenar alfabéticamente Ordenar por aportación de la UE Ampliar todo Contraer todo UNIVERSITA DEGLI STUDI DI ROMA TOR VERGATA Italia Aportación de la UE € 1 496 200,00 Dirección VIA CRACOVIA 50 00133 Roma Ver en el mapa Región Centro (IT) Lazio Roma Tipo de actividad Higher or Secondary Education Establishments Investigador principal Roberto Testi (Prof.) Contacto administrativo Giuseppe Novelli (Prof.) Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Coste total Sin datos