Investigating the structure of amyloid fibrils using mass spectrometry

The pathogenesis of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson's disease and amyotrophic lateral sclerosis, is believed to be caused by the aggregation of non-native proteins. One such protein that forms fibril (amyloid) aggregates is alpha-synuclein, which is heavily associated with Parkinson's disease. My current focus is on understanding the role lipids play in the aggregation dynamics of alpha-synuclein using a range of mass spectrometry-based approaches. Native MS is a high-resolution tool utilised in structural biology which can define a range of structural features within proteins, such as oligomeric distribution and polydispersity (using collision-induced dissociation-MS; CID-MS), unfolded/unstructured states (tertiary structure), assembly stability (using collision-induced unfolding-MS) and quaternary conformation of proteins (the latter two via. ion-mobility – MS). Using these techniques, in conjunction with other biophysical tools, can provide a structural rationale for protein function/dysfunction.