Obiettivo Huntington´s disease (HD) is an incurable and fatal neurodegenerative disease, manifested by a progressive loss of neurons, causing neuronal motor dysfunction, cognitive decline and death. The disease is caused by a CAG repeat expansion in the Huntingtin (HTT) gene. The CAG expansion induces a neurotoxic effect, mainly thought to be caused by the expanded protein. However, also expanded RNA transcripts can cause toxicity by generation of small CAG-repeated RNAs. Generation of these small RNAs depends on Dicer ribonuclease activity and their toxic effects are modulated by Ago proteins. This links RNA toxicity with the RNA interference (RNAi) pathway, suggesting abnormal induction of gene silencing through small-repeated RNAs.The DNA damage response (DDR) plays a role in HD pathogenesis as well. Recently, it was shown that small RNAs derived from Dicer and Drosha processing can induce and control this response. The goal of this project is to address the possible link between small CAG-repeated RNA toxicity and the DDR pathway in HD.We hypothesize that small RNAs activate a DDR response and thereby induce neurotoxicity. We will address this by the following objectives: 1) Establish whether CAG-repeated RNAs activate the DDR pathway, 2) Establish whether DDR inhibition can modulate small RNA toxicity and whether DDR activation is RNAi pathway dependent, 3) Validation of our results using in vivo and ex vivo samples. We will use in vitro cell models combined with ex vivo brain samples from HD affected mice and humans. The effect of small CAG-repeated RNAs on activation of the DDR response will be analyzed by western blot, immuno-fluorescence and immuno-histochemistry. Small RNA pool analysis, knockdown studies and lentiviral transfection approaches will be used to reveal the specificity of the effect and the RNAi pathway dependence.This project will contribute to a better understanding of HD pathogenesis, RNA biology, small RNA toxicity and the DDR pathway. Campo scientifico natural sciencesbiological sciencesgeneticsDNAnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsnatural sciencesbiological sciencesgeneticsRNA Programma(i) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Argomento(i) FP7-PEOPLE-2012-IEF - Marie-Curie Action: "Intra-European fellowships for career development" Invito a presentare proposte FP7-PEOPLE-2012-IEF Vedi altri progetti per questo bando Meccanismo di finanziamento MC-IEF - Intra-European Fellowships (IEF) Coordinatore FUNDACIO CENTRE DE REGULACIO GENOMICA Contributo UE € 173 370,60 Indirizzo CARRER DOCTOR AIGUADER 88 08003 Barcelona Spagna Mostra sulla mappa Regione Este Cataluña Barcelona Tipo di attività Research Organisations Contatto amministrativo Olga Juderias (Ms.) Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Costo totale Nessun dato