GWBioMedMRC DLP PhD project: Boosting Brain Cell Recycling System: Peptide Activation of TFEB

Supervisory Team:

Prof Jody Mason (University of Bath)

Dr Bernadette Carroll (University of Bristol)

Prof Matt Crump (University of Bristol)

Can we help brain cells clear harmful proteins by boosting their own recycling machinery? This PhD will explore a new approach to that question: designing peptides that directly activate TFEB, a protein that controls cellular waste clearance.

Neurodegenerative diseases, including Parkinson’s disease, are associated with the accumulation of damaged proteins and defective cellular components. Neurons depend on autophagy, which collects unwanted material, and lysosomes, which break it down and recycle it. TFEB switches on genes that support these processes. Increasing its activity could therefore help restore cellular waste clearance. However, many existing approaches act indirectly through pathways that control numerous other cellular functions.

This project will investigate whether peptides, short chains of amino acids, can bind TFEB directly and stabilise complexes that increase its activity. You will combine molecular design, biochemical experiments and cell biology to test whether this strategy improves recycling and the clearance of disease-associated proteins in neuronal cell models.

You will pursue three linked objectives:

Building on pilot work in the Mason laboratory, you will use computational design, including Insili Coil, and intracellular peptide library screening to identify promising sequences. You will produce recombinant TFEB and use sequencing data from peptide screens to prioritise candidates for synthesis and testing. Comparing linear, cell-penetrating and structurally constrained peptides will help establish how their sequence, shape, stability and ability to enter cells influence activity.

You will determine how lead peptides bind TFEB and affect its assembly and recognition of DNA. Training will include protein biochemistry and biophysical methods such as circular dichroism, fluorescence polarisation and DNA-binding assays. Working with Professor Matt Crump at Bristol, you will use nuclear magnetic resonance spectroscopy and, where appropriate, X-ray crystallography to investigate peptide–TFEB interactions. These experiments will guide peptide optimisation and distinguish productive TFEB activation from non-specific effects on proteins or cellular stress.

Working with Dr Bernadette Carroll at Bristol, you will test promising peptides in cellular models relevant to neurodegeneration. You will assess TFEB activity, expression of its target genes, lysosomal function and autophagic flux, which measures material passing through the recycling pathway. You will also investigate whether the peptides improve clearance of disease-associated proteins such as α-synuclein, which accumulates in Parkinson’s disease.

Together, these experiments will establish whether direct TFEB engagement produces the intended biological response inside cells.

Based at the University of Bath, with specialist training at Bristol, you will develop skills spanning peptide design, molecular biology, protein biochemistry, structural analysis and neuroscience. During the initial three-month preparation period, you will review the literature and pilot data, identify your training needs and help shape the experimental plan. As the project develops, you can steer it towards peptide optimisation, structural mechanisms or cellular responses, according to your interests and the findings.

The project welcomes applicants from biochemistry, biomedical sciences, neuroscience, molecular biology, pharmacology,…