Mechanisms of human co-translational quality control and it’s role in neural tissue.

Introduction

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.

Importance of RQC

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.

Background of the Project

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.

Methodology

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.

Objectives

We will:

1. Define working principles of RQC components.
2. Investigate the mechanisms by which their disease-causing mutations specifically affect neurons in vivo using C. elegans as a model organism.

Approach

Our approach utilizes a multidisciplinary strategy 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.

Significance

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.