RNA biology: investigating the role of UPF1 in mRNA Processing and Neurodegenerative Diseases

Accurate gene expression is fundamental to the survival of all life forms. RNA helicases, a large family of enzymes, are key regulators involved in several stages of this process, including transcription, pre-mRNA processing, and translation. One of these helicases, UPF1, has been extensively studied and is highly conserved across eukaryotes. Traditionally, UPF1 was thought to be primarily involved in the cytoplasm, regulating translation and mediating nonsense-mediated mRNA decay (NMD) (1). However, recent findings have broadened our understanding of UPF1’s function.

Our recent studies have demonstrated that UPF1 shuttles dynamically between the nucleus and the cytoplasm, playing a much broader role than previously understood. Crucially, UPF1 associates with nascent pre-mRNA transcripts, indicating that it has genome-wide roles in nuclear RNA-based processes, such as Pol II transcription, pre-mRNA splicing, mRNA release from the transcription site, and export to the cytoplasm. These novel insights reshape the current understanding of UPF1’s role in gene expression, suggesting that UPF1 is also involved in regulatory pathways essential for RNA homeostasis and stability across evolutionarily diverse organisms (2, 3).

One particularly exciting area of research concerns UPF1’s role in preventing or modifying neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Preliminary data from our lab have shown that UPF1 depletion leads to the accumulation of RNA aggregates within the nucleus—a hallmark of neurodegeneration. These findings raise the possibility that UPF1 plays a critical role in the cellular response to neurodegenerative stressors, offering a potential target for therapeutic intervention.

Broadly the aim of this PhD project is to further our understanding of UPF1’s multifaceted role in mRNA production and its potential involvement in mitigating the effects of neurodegenerative disorders. In this project the student will use a multidisciplinary approach ()to study these questions in amenable model organisms, such as Drosophila or fission yeast, the student can decide whether to work with one or the other (the lab has expertise with both). This project will provide expertise in Molecular Cell Biology, Genetics, and Bioinformatics, and will involve collaborations with other leading research groups.