Studies of amyloid beta and alpha-synuclein oligomerisation by microfluidic techniques

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Alzheimer's (AD) and Parkinson's (PD) diseases are increasingly prevalent and currently incurable neurodegenerative disorders linked to the accumulation of proteinaceous pathogenic inclusions in the nerve system. Oligomerisation of misfolded amyloid beta and alpha-synuclein proteins is a key step in AD and PD-associated neurotoxicity. Therefore a detailed understanding of this phenomenon is crucial to find effective disease management and therapeutic strategies. However, despite the intensive effort put to understand aberrant protein oligomerisation and the downstream events, mechanistic details of oligomer-induced cellular toxicity are still missing. The project aims at characterising AD- and PD- relevant oligomers at a single-molecule level, to the level of depth and complexity inaccessible by conventional biophysical techniques before. The project outcomes will fill in the gap of knowledge in disease-linked oligomer formation, evolution, diversity, interactions with cellular binding partners and, importantly, implications in neurotoxicity. A set of microfluidic techniques combined with an advanced single-molecule optical detection strategy will be employed to address the challenges faced in biophysical oligomer characterisation studies, namely transient nature, heterogeneity and low abundance of the species. The work will be carried out in close collaboration with Fluidic Analytics Ltd, a company developing and commercialising novel microfluidic tools for protein biophysics. The project is highly interdisciplinary and lies in the areas of biophysics and soft matter physics, as well as chemical biology and biological chemistry.