Catalytic activity of alpha-synuclein amyloid fibers

Research Project, 2024 – 2027

Protein assembly into ordered amyloids are hallmarks of neurodegenerative disorders. All amyloids have a common overall arrangement of beta-strands perpendicular to the fiber axis, but the actual fold (polymorph) depends on sequence and conditions. Here, we will investigate a new function for amyloids that may dramtically influence how we view amyloid diseases in the future. Based on recent pioneering work, amyloid fibers can act like enzymes and catalyze chemical reactions. We will explore this concept using alpha-synuclein, the amyloidogenic protein in Parkinson’s disease in combination with protein engineering, biophysical tools and cell biology. We will test catalytic activity towards selected chemical reactions in vitro as a function of amyloid structure and chemistry. In addition, using metabolomics, we will identify neuronal cell metabolites chemically transformed in the presence of alpha-synuclein amyloids, followed by verification in vitro. Finally, to probe the biological relevance of this new activity, we will study alpha-synuclein amyloid catalysis directly inside living cells.  This project will provide novel insights around a new functionality of amyloid fibers not considered before. If amyloids can directly affect disease progression by changing the metabolic status in cells, this is important to consider in drug developments. It is also of fundamental interest as this may be an overlooked property of most amyloid systems in biology.