RNA stress and neurodegeneration: how UPF1 protects cells from harmful RNA accumulation

About the Project

RNA biology is emerging as a central theme in neurodegenerative disease. In ALS, FTD and related disorders, disruption of RNA processing, RNA-binding proteins and RNA-protein assemblies can lead to harmful aggregates and loss of cellular resilience. This PhD project will investigate how the conserved RNA helicase UPF1 helps cells process, release and protect messenger RNAs, and how failure of this system may contribute to stress and neurodegeneration.

The project is based in the School of Biosciences at the University of Birmingham, in the laboratory of Professor Saverio Brogna. It builds on long-standing work from the Brogna lab showing that UPF1 is not only a factor in nonsense-mediated mRNA decay, but also acts more broadly during transcription, mRNA processing and mRNA release from gene loci.

Recent preliminary observations suggest that depletion of UPF1 can lead to the accumulation of nuclear RNA aggregates. This raises a simple but important question: how does UPF1 help cells keep newly made RNAs in a productive, non-toxic state?

The student will investigate how UPF1 acts on nascent mRNAs and ribonucleoprotein particles, using genetically tractable model systems such as fission yeast and Drosophila. The project can be shaped around the student's interests, with scope for molecular genetics, RNA biology, microscopy, transcriptomics and computational analysis.

Key questions include:

• How does UPF1 act during transcription, RNA processing and mRNA export?
• Which RNA and protein partners define UPF1-dependent ribonucleoprotein complexes?
• Does loss of UPF1 promote nuclear RNA aggregates or stress responses?
• What can model systems reveal about conserved RNA quality-control mechanisms relevant to neurodegeneration?

The student will receive training in molecular genetics, RNA purification and analysis, CRISPR-based approaches, fluorescence microscopy, FISH, RNA-seq or related high-throughput methods, and bioinformatic analysis of sequencing or imaging data.

This project would suit a curious and motivated student with a background in molecular biology, genetics, genomics, neuroscience, bioinformatics or computational biology. Full training will be provided. The project offers the opportunity to develop a strong profile in fundamental RNA biology while working on a question with clear relevance to human disease.

The Brogna lab has expertise in RNA processing, translation, nonsense-mediated decay, ribosomes, Drosophila genetics, fission yeast molecular biology, microscopy and genome-wide approaches. The student will join an active RNA biology environment with regular supervision, weekly lab meetings and opportunities to develop independent ideas.

Initial contact: please email a CV and a brief statement of research interests to s.brogna@birmingham.ac.uk.

Formal PhD applications should be submitted through the University of Birmingham Biosciences PhD application route: https://www.birmingham.ac.uk/study/postgraduate/subjects/biosciences-courses/biosciences-phd