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. 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 molecular understanding of CAT tailing and nascent chain degradation in human RQC. We will define working principles of human RQC components and the mechanisms by which their disease-causing mutations specifically affect neurons.
Results of the project will provide detailed functional understanding of the critical RQC system and unravel processes leading to pathological changes in human neurodegenerative diseases. Our results will thus have implications for human health and the potential to reveal novel drug targets.

Sustainable Development Goals

Masaryk University is committed to the UN Sustainable Development Goals, which aim to improve the conditions and quality of life on our planet by 2030.