Descrizione del progetto
RNA e aggregati ribonucleoproteici nei neuroni
Studi recenti indicano l’implicazione della rilevanza patogenetica del metabolismo dell’RNA alterato e dell’assemblaggio ribonucleoproteico (RNP) anomalo in molte malattie neurodegenerative. Il modo in cui si formano gli RNP difettosi, quali siano i loro componenti integrali e quali eventi vengano innescati dalla loro apparizione in età avanzata, rimangono questioni irrisolte. Il progetto ASTRA, finanziato dall’UE, combinerà una sofisticata depurazione del complesso ribonucleoproteico imaging-derivato a strumenti genetici e approcci di calcolo innovativi, per studiare le proprietà biofisiche e la composizione dei complessi nonché il modo in cui sono modificati in condizioni patologiche. Lo sviluppo di nuovi metodi ottici e di imaging permetterà agli scienziati di studiare la separazione degli RNP in fasi liquide e solide di cellule, tessuti e modelli animali, e di caratterizzare i loro componenti di RNA e proteine negli stati fisiologici e patologici.
Obiettivo
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.
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Meccanismo di finanziamento
ERC-SyG - Synergy grantIstituzione ospitante
00185 Roma
Italia