MSc by Research: Molecular Glues for ALS: Restoring TDP-43 Localization for drug discovery

About the Project

Proteins rarely function in isolation; instead, they form biomolecular complexes by interacting with other biomolecules, including DNA, RNA, and proteins. One such protein is TDP-43, an RNA-binding protein. In amyotrophic lateral sclerosis (ALS), TDP-43 is mislocalized to the cytosol, leading to protein aggregation and neurotoxicity. While advances in molecular cell biology have illuminated aspects of TDP-43’s role in ALS, its mislocalization remains poorly understood due to a lack of effective chemical tools that specifically target TDP-43. This Master’s project aims to develop molecular glues to restore TDP-43 localization to the nucleus, enabling studies on its role in ALS and supporting the development of a new drug modality.

In this joint Master’s project between the McGurk and Cossar Labs, you will integrate molecular biophysics, drug screening approaches, and structural biology to develop chemical tools that stabilize TDP-43 in a biomolecular complex. Specifically, you will:

1. Biophysically and structurally characterize TDP-43 in complex with its RNA substrate.
2. Identify and optimize drug-like chemical matter that targets protein-RNA and protein-protein complexes, and characterize their binding.
3. Investigate how small molecules mediate the relocalization of TDP-43.

You will be based in the Cossar Lab within the Centre for Targeted Protein Degradation, a multidisciplinary environment with world-class facilities. This project will develop your expertise in molecular biophysics, organic chemistry, and chemical and structural biology. The lab employs molecular glue-, covalent-, and fragment-based drug discovery approaches to address fundamental molecular biology questions, providing a comprehensive training experience.

You will collaborate closely with the McGurk Lab within the Division of Cell and Developmental Biology. The McGurk Lab applies a range of techniques, including fruit fly genetics, in vitro biochemistry, and mammalian cell and neuronal culture systems, offering exposure to diverse biological methodologies.

Ideal applicants will have a strong interest in drug discovery and molecular biophysics. Prior experience in protein production or organic synthesis is preferred but not essential. The project can be tailored to your specific interests, and you will receive personalized mentorship to enhance your technical skills and professional development.

The University of Dundee’s inclusive research community offers an excellent setting for ambitious individuals. We welcome applications from all talented candidates, especially those with the drive and potential to make significant contributions to the field of drug discovery.

Our research community thrives on the diversity of students and staff which helps to make the University of Dundee a UK university of choice for postgraduate research. We welcome applications from all talented individuals and are committed to widening access to those who have the ability and potential to benefit from higher education.