Projektbeschreibung
RNA- und Ribonukleoprotein-Aggregate in Neuronen
Neuere Studien implizieren die pathogene Relevanz eines veränderten RNA-Stoffwechsels und eines abweichenden Ribonukleoproteinzusammenbaus (RNP) bei verschiedenen neurodegenerativen Erkrankungen. Wie defekte Ribonukleoproteine entstehen, was ihre integralen Bestandteile sind und welche Ereignisse ihr Auftreten im späten Leben auslösen, sind immer noch ungeklärte Fragen. Das EU-finanzierte Projekt ASTRA wird eine hochentwickelte, aus der Bildgebung abgeleitete Ribonukleoprotein-Komplexreinigung, genetische Instrumente und innovative rechnergestützte Ansätze kombinieren, um die biophysikalischen Eigenschaften und die Zusammensetzung der Komplexe und wie diese unter den Bedingungen von Erkrankungen modifiziert werden, zu untersuchen. Die Entwicklung neuer bildgebender und optischer Methoden wird es der Wissenschaft ermöglichen, die Trennung von Ribonukleoproteinen in flüssige und feste Phasen innerhalb der Zellen, in Geweben und Tiermodellen zu untersuchen und deren RNA- und Proteinkomponenten im physiologischen und pathologischen Zustand zu charakterisieren.
Ziel
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.
Wissenschaftliches Gebiet
Schlüsselbegriffe
Programm/Programme
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Finanzierungsplan
ERC-SyG - Synergy grantGastgebende Einrichtung
00185 Roma
Italien