Despite the prevalence of Parkinson’s disease in today’s society, therapies remain remote due to limited understanding of the discrete molecular processes involved in protein aggregation. I am a biochemist particularly interested in the early aggregation of alpha-synuclein (α-syn), an amyloidogenic precursor protein involved in the pathogenicity of Parkinson’s disease. I completed my undergraduate degree at Sheffield Hallam University with a placement year at the Institute for Lung Health, Leicester. At Sheffield Hallam I was exposed to leading mass spectrometry research and introduced to the fascinating subject of amyloid aggregation by Dr David Smith. I wanted to pursue a PhD under the supervision of Professor Sheena Radford, a leader in the field of amyloid aggregation at the Astbury Centre for Structural Molecular Biology, the University of Leeds and Professor Frank Sobott, a leader in the application of mass spectrometry for biomolecular structural characterisation.
α-Syn is an intrinsically disordered protein, however it’s radius of gyration is smaller than estimated for a random coil of the same size. This is suggestive of partial mediation of some secondary structure through long-range intramolecular hydrophobic and electrostatic interactions. Regions in the N-terminal region of the protein chain have been identified as mediators of aggregation, responsible for intramolecular interactions that shift the conformational ensemble to an aggregation prone state. In my project I will be using a combination of mass spectrometry (MS) techniques to structurally interrogate the conformational dynamics of α-syn.
There are a plethora of state-of-the-art MS techniques available at the Astbury centre established for investigating protein folding/unfolding, protein kinetics, protein-protein interactions and protein-ligand binding. These include native mass spectrometry, ion mobility spectrometry, chemical cross linking, and hydrogen-deuterium exchange. I will be using ion-mobility MS to establish the collisional cross section of α-syn and to structurally distinguish conformations of α-syn that favour aggregation, supported by listed hybrid mass spectrometry techniques as well as biophysical and biochemical techniques. Such insights are key to understanding the discrete molecular mechanisms involved in early aggregation, essential to develop therapeutic strategies.