Descripción del proyecto
El papel de la traducción RAN en la neurodegeneración
El síndrome de temblor y ataxia asociado al cromosoma X frágil (FXTAS, por sus siglas en inglés) es una enfermedad neurodegenerativa hereditaria causada por la expansión de repeticiones del triplete de nucleótidos citosina-guanina-guanina (CGG) en la región no codificante del gen 1 del retraso mental asociado al cromosoma X frágil 1 (FMR1). Numerosos indicios revelan que la traducción sin ATG asociada a repeticiones (del inglés «repeat associated non-AUG» o RAN) está implicada en la patogenia del FXTAS, ya que favorece la síntesis de proteínas tóxicas que se acumulan en las neuronas y provocan su muerte. El objetivo de los investigadores del proyecto financiado con fondos europeos Prot-RAN es identificar proteínas implicadas en el inicio y la elongación de la traducción RAN mediante el uso de tecnologías punta. El trabajo proporcionará una perspectiva más completa de la traducción RAN y permitirá identificar dianas terapéuticas potenciales para trastornos relacionados con la expansión del número de repeticiones de tripletes de nucleótidos como el FXTAS, la enfermedad de Huntington, la ataxia espinocerebelosa y la distrofia miotónica.
Objetivo
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.
Ámbito científico
Palabras clave
Programa(s)
Convocatoria de propuestas
Consulte otros proyectos de esta convocatoriaConvocatoria de subcontratación
H2020-WF-02-2019
Régimen de financiación
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinador
61 712 POZNAN
Polonia