NeuroQuality
Financiado
Mechanisms of human co-translational quality control and it’s role in neural tis...
Ribosome-associated quality control (RQC) is crucial for degrading truncated nascent proteins produced on aberrant mRNAs. This is done by elongation of the nascent chain on the large ribosomal subunit in the absence of mRNA and th...
Ribosome-associated quality control (RQC) is crucial for degrading truncated nascent proteins produced on aberrant mRNAs. This is done by elongation of the nascent chain on the large ribosomal subunit in the absence of mRNA and the small ribosomal subunit (CAT tailing) and by marking the nascent chain for degradation. Mutations in RQC components cause neurodegeneration both in animal models and human patients. Moreover, RQC insufficiency and subsequent protein aggregation critically contribute to proteostasis impairment and systemic decline during ageing. Strikingly, we lack mechanistic understanding of this crucial process in humans.
This project stems from my post-doctoral research, in which I have solved the structure of the yeast RQC complex and discovered a novel RQC factor, the eIF5A. This conserved protein is critical in yeast RQC and was recently implicated in brain development and Huntington's disease. Moreover, I have developed a human cell-free translation extract, which enables structural studies of co-translational processes in the human system. In the proposed research, we will provide mechanistic understanding of CAT tailing and nascent chain degradation in human RQC using cryo-EM. We will define working principles of RQC components and the mechanisms by which their disease-causing mutations specifically affect neurons in vivo using the C. elegans as a model organism.
Our approach utilizes a multidisciplinary approach to provide detailed mechanistic understanding of the critical RQC system in combination with an in vivo study to reveal processes leading to RQC-driven pathological changes in neural tissue. Since the RQC pathway is conserved in all kingdoms of life and serves a pivotal role in protein homeostasis with critical implications for neurodegenerative disorders and ageing, our findings will have important implications for human health and the potential to reveal novel drug targets.
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Duración del proyecto: 68 meses
Fecha Inicio: 2023-10-02
Fecha Fin: 2029-06-30
Fecha Fin: 2029-06-30
Línea de financiación: concedida
El organismo HORIZON EUROPE notifico la concesión del proyecto el día 2023-10-02
Línea de financiación objetivo
El proyecto se financió a través de la siguiente ayuda:
ERC-2023-STG:
ERC STARTING GRANTS
Cerrada
hace 2 años
Presupuesto
El presupuesto total del proyecto asciende a
2M€
Líder del proyecto
Masarykova univerzita
No se ha especificado una descripción o un objeto social para esta compañía.
Perfil tecnológico
TRL
4-5
Perfil tecnológico
TRL
4-5
100.00K€ |
Participante