Ordering the disordered in Parkinson's disease to derive peptide inhibitors of alpha-synuclein toxicity

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The student will develop peptides that can be used to effectively block formation of a toxic protein responsible for thepathology of Parkinson's disease (PD). The protein, known as alpha-synuclein (aS), self-associates inside dopamineproducing cells in the brain to form toxic clumps known as Lewy bodies that interfere with normal brain function, leadingto the symptoms of the disease. We will inhibit this process building from a system that we have demonstrated to work(Meade et al J Mol Biol 2021, 2022, Watt et al ACS Chem Neurosci 2022, Watt et al J Biol Chem 2022). Using a novelscreening system that targets the natural folded state of aS, that is prior to misfolding and aggregation, the student willscreen large peptide libraries (>2 Million members) inside living bacterial cells. In this assay, inhibitors are only selected ifthe very first step in aggregation is blocked, leading to a restoration of cell viability. The student will use the screening assay to generate numerous inhibitory peptides to block the very first steps in themisfolding of aS. This will provide a wide range of sequences from which we can understand the mechanism of inhibitionvia biophysical, neuronal cell-based, and structural biology methods. Our overarching aim is to assign function to specificsequence elements within our newly generated inhibitors to demonstrate the principles of rational inhibitor design,ultimately improving the properties of future peptide generations. Finally, by comparing endogenously produced toexternally added peptides, the student will begin to explore aspects of drug delivery, such as permeability to reachintracellular targets. The composition of the supervisory team ensures comprehensive expertise in all facets of thisinterdisciplinary project. The training environment will be highly supportive and stimulating, including ampleopportunity for wider engagement with the scientific community. You will be guided through the challenges andrewards of this project while gaining a wide range of skills that are translatable to many other systems.