Description du projet
Des agrégats d’ARN et de ribonucléoprotéines dans les neurones
De récentes études mettent en cause la pertinence pathogène du métabolisme de l’ARN altéré et de l’assemblage de ribonucléoprotéines (RNP) aberrantes dans plusieurs maladies neurodégénératives. La manière dont les RNP défectueuses se forment, l’identification de leurs composants intégraux et des évènements qui déclenchent leur apparition plus tard dans la vie sont encore des questions pour lesquelles les réponses manquent. Le projet ASTRA, financé par l’UE, combinera une purification complexe des RNP élaborée et dérivée de l’imagerie, des outils génétiques et des approches de calcul novatrices pour examiner les propriétés biophysiques et la composition des complexes et la manière dont elles évoluent selon les maladies. Le développement de nouvelles méthodes d’imagerie et d’optique permettra aux scientifiques d’étudier la séparation des RNP en phases liquide et solide dans les cellules, les tissus et les modèles animaux, et de caractériser leurs composants ARN et protéiques dans des états physiologiques et pathologiques.
Objectif
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.
Champ scientifique
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Programme(s)
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Régime de financement
ERC-SyG - Synergy grantInstitution d’accueil
00185 Roma
Italie