Abstrakt
Aggregation of the neuronal protein alpha-synuclein into amyloid fibrils plays a central role in the development of Parkinson's disease. Growth of fibrils can be suppressed by blocking fibril ends from their interaction with monomeric proteins.
In this work, we constructed inhibitors that bind to the ends of alpha-synuclein amyloid fibrils with very high affinity. They are based on synthetic alpha-synuclein dimers and interact with fibrils via two monomeric subunits adopting conformation that efficiently blocks fibril elongation.
By tuning the charge of dimers, we further enhanced the binding affinity and prepared a construct that inhibits fibril elongation at nanomolar concentration (IC50 approximate to 20 nM). To the best of our knowledge, it is the most efficient inhibitor of alpha-synuclein fibrillization.