Description du projet
Le rôle de la traduction RAN dans la neurodégénérescence
Le syndrome de tremblement/ataxie associé à l’X fragile (FXTAS) est une maladie neurodégénérative héréditaire causée par l’expansion des répétitions CGG dans la région non codante du gène X fragile de retard mental 1 (FMR1). De nouvelles preuves indiquent que la traduction répétée associée non-AUG (RAN) est impliquée dans la pathogenèse FXTAS en produisant des produits protéiques toxiques qui s’accumulent dans les cellules neuronales, provoquant la mort. Les chercheurs du projet Prot-RAN, financé par l’UE, visent à identifier les protéines impliquées dans l’initiation et l’allongement de la traduction RAN en utilisant des technologies de pointe. Les travaux fourniront une vision plus globale de la traduction RAN et dévoileront des cibles thérapeutiques potentielles pour les troubles d’expansion répétée tels que le FXTAS, la maladie de Huntington, les ataxies spinocérébelleuses ou la dystrophie myotonique.
Objectif
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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MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinateur
61 712 POZNAN
Pologne