Ligand profiling to characterise different polymorphic forms of α-synuclein aggregates.

The presence of amyloid fibrils is a characteristic feature of many diseases, most infamously neurodegenerative disease. The supramolecular structure of these fibrils appears to be disease-specific. Identifying the unique morphologies of amyloid fibrils could therefore form the basis of a diagnostic tool. Here we report a method to characterise the morphology of α-synuclein (αSyn) fibrils based on profiling multiple different ligand binding sites that are present on the surfaces of fibrils. By employing various competition binding assays, seven different types of binding sites were identified on four different morphologies of αSyn fibril. Similar binding sites on different fibrils were shown to bind ligands with significantly different affinities. We combined this information to construct individual profiles for different αSyn fibrils based on the distribution of binding sites and ligand interactions. These results demonstrate that ligand-based profiling can be used as an analytical method to characterise fibril morphologies with operationally simple fluorescence binding assays.Cambridge Trust Prince of Wales Scholarship, and the EPSRC Underpinning MultiUser Equipment Call (EP/P030467/1)