Descripción del proyecto
ARN y complejos de ribonucleoproteínas en neuronas
Estudios recientes ponen de manifiesto la importancia patógena de la alteración del metabolismo del ARN y del ensamblaje anómalo de ribonucleoproteínas (RNP) en varias enfermedades neurodegenerativas. Cómo se forman las RNP defectuosas, cuáles son sus componentes principales y qué procesos desencadenan su aparición en una etapa tardía de la vida son preguntas que aún carecen de respuesta. El proyecto financiado con fondos europeos ASTRA combinará una técnica sofisticada de purificación de complejos de RNP mediante imagenología, herramientas genéticas y métodos computacionales innovadores para investigar las propiedades biofísicas y la composición de los complejos y cómo se modifican en procesos patológicos. El desarrollo de nuevos métodos ópticos y de imagenología permitirá a los científicos estudiar la separación de las RNP en fases líquidas y sólidas en células, tejidos y modelos animales, así como caracterizar sus componentes de ARN y proteínas en estados fisiológicos y patológicos.
Objetivo
Recent works indicate the pathogenic relevance of altered RNA metabolism and aberrant ribonucleoprotein (RNP) assembly in several neurodegenerative diseases, such as Amyotrophic lateral sclerosis. How defective RNPs form, what are their integral components and which events trigger their appearance late in life are still unsolved issues. While emerging evidence indicates that mutations and post-translational modifications of specific RNA-binding proteins (RBPs) induce liquid-solid phase transition in vitro, much less is known about the in vivo properties of RNP assemblies and which role RNA plays in their formation.
ASTRA will combine sophisticated imaging-derived RNP complex purification with innovative computational approaches and powerful genetic tools to unravel the biophysical properties and composition of RBP complexes and how they are modified in disease conditions. Through the development of new imaging and optical methods we plan to study how RNPs separate in liquid and solid phases in cells, in tissues (retina) and animal models and to characterize their RNA and protein components in physiological and pathological states.
Exploiting the novel finding that non-coding RNAs act as scaffolding molecules for RNP assembly, we will investigate how such RNAs control the dynamic link between RNP formation, intracellular sorting and function. In a genuine interdisciplinary team effort, we will reveal how the architecture and localization of cytoplasmic RNP complexes are controlled in motor neurons and affected in neurodegeneration.
We plan to develop novel advanced microscopy methods to monitor formation of aberrant RNPs in vivo and we will explore new molecules to impede pathological cascades driven by RNP assemblies. In conclusion, ASTRA will allow us to gain a comprehensive understanding of RNP function and dysfunction; we will use this knowledge to develop new therapeutic strategies that will impact on several protein-misfolding neurodegenerative diseases.
Ámbito científico
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Programa(s)
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Régimen de financiación
ERC-SyG - Synergy grantInstitución de acogida
00185 Roma
Italia