Descrizione del progetto
Il ruolo della traduzione RAN nella neurodegenerazione
La sindrome da tremore/atassia associata all’X fragile (FXTAS, fragile X-associated tremor/ataxia syndrome) è una malattia neurodegenerativa ereditaria causata dall’espansione delle ripetizioni CGG nella regione non codificante del gene del ritardo mentale da X fragile 1 (FMR1). Evidenza emergente indica che la traduzione non avviata con AUG associata a ripetizione (RAN, repeat associated non-AUG initiated) è implicata nella patogenesi FXTAS producendo prodotti proteici tossici che si accumulano nelle cellule neuronali, causando la morte. Gli scienziati del progetto Prot-RAN, finanziato dall’UE, mirano a identificare le proteine coinvolte nell’avvio e nell’allungamento della traduzione RAN utilizzando tecnologie all’avanguardia. Il lavoro fornirà una visione più globale della traduzione RAN e svelerà i potenziali obiettivi terapeutici per i disturbi di espansione ripetuti come la FXTAS, il morbo di Huntington, le atassie spinocerebellari o la distrofia miotonica.
Obiettivo
The short tandem repeats are common in human genome, but their uncontrolled expansions may lead to several inherited disorders. In Prot-RAN project, I will focus on the expansion of trinucleotide CGG repeats (CGGexp) in the 5’UTR of fragile X mental retardation 1 (FMR1) gene, which causes common neurodegenerative disease, known as fragile X-associated tremor/ataxia syndrome (FXTAS). The pathogenesis of FXTAS remains unclear, and one of the possible mechanisms, the repeat associated non-AUG initiated (RAN) translation, can be shared in majority of microsatellite expansion diseases, as it was already linked to 9 different disorders. In FXTAS, the CGGexp enhances RAN translation from the 5’UTR of FMR1 mRNA, what leads to the production of toxic polyglycine or polyalanine containing proteins. These aberrant products accumulate in nuclear inclusions in the brain of FXTAS patients, impairing the nuclear lamina architecture and leading to neuronal death. The RAN translation mechanism is still not well understood; therefore, in the proposed project I will identify and investigate the role of proteins implicated in RAN translation initiation/elongation. To achieve this goal, I will benefit from the synergy between my long-time experience in mass spectrometry and the expertise of the host lab in RNA biology, and I will bridge cutting-edge proteomics with RNA biology techniques. Briefly, I will employ the CGGexp RNA-targeting pull-down approaches combined with proteomic profiling, RNA mutagenesis, high throughput protein expression analysis and RNA/protein interaction studies in a context of their functional implications. The role of identified proteins will be then verified in other expansion disorders, e.g. Huntington’s disease, giving insight into more global view of the RAN translation. As a result, the discovered factors driving RAN translation and knowledge of mechanism of their action could be used as potential new targets for therapeutic strategies.
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Meccanismo di finanziamento
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinatore
61 712 POZNAN
Polonia