New tools to study disease-related protein fibril growth and inhibition

Supervisory team:
Dr Adam Squires, Department of Chemistry
Dr Jody Mason, Department of Biology & Biochemistry

This project is a collaboration between Dr A Squires (Chemistry) and Dr J Mason (Biology & Biochemistry). The student will advance the development of biophysical methods pioneered in the Squires lab to study amyloid protein aggregation, and apply them to therapeutic small peptide-based aggregation inhibitors for Parkinson’s disease, rationally designed by a peptide fragment library screening system developed in the Mason group. The student will develop novel isotope labelling strategies for polarised vibrational spectroscopy and neutron scattering to obtain previously unobtainable data on fibril growth rates in solution and molecular arrangement within fibrils. Using these tools, they will elucidate the mode of action of the therapeutic inhibitors, with additional complementary biophysical methods based on fluorescence assays, NMR, mass spectrometry, and small-angle x-ray scattering using Bath’s new small-angle x-ray scattering instrument. They will use the resulting data to address key questions: how do therapeutic peptides inhibit aggregation? (By preventing formation of new fibril “seeds” or slowing down their subsequent growth?) What is the structural and energetic basis for peptide binding? Towards which (non-toxic) species does the peptide drive the α-synuclein?

In addition to the insights gained into this potentially important class of therapeutic agent, the project will develop and demonstrate experimental tools applicable more generally to a range of systems in biophysics and soft matter.
The student will learn protein expression, and a range of biophysical techniques, including small-angle neutron and x-ray scattering in Bath and at national facilities.