LAUSR

The aggregation process, going from monomers to amyloid fibers, of the protein α-synuclein (αS) somehow causes degeneration of dopaminergic neurons in Parkinson's disease patients. The exact activities of αS are not yet identified, but synapse vesicle formation and transport have been proposed. αS binds strongly to vesicles made of negatively charged lipids in vitro and such interactions may thus play a role in vivo. Probably because of variations in experimental conditions, vesicle binding has been reported to both trigger and block αS amyloid formation in vitro. As the cell environment is highly crowded with biomolecules, in addition to membranes, interactions with other aggregation-prone proteins may modulate αS amyloid formation in vivo. To better understand how interactions with other biomolecules, that may take place in vivo, may modulate αS amyloid formation, we have employed an array of biophysical tools (circular and linear dichroism, fluorescence, light scattering, and imaging methods) to probe αS amyloid formation as a function of lipid vesicles (of different composition and lipid-to-protein ratios) and the amyloid-forming peptide in type-2 diabetes, IAPP (in pro-peptide and processed forms; as monomer or amyloid seed). Our results underscore the importance of considering cross-reactivity effects in Parkinson's disease. For example, we revealed that at lipid-to-protein ratios where only a fraction of αS is bound, vesicles can completely remove the lag time of αS amyloid formation and the resulting amyloid fibres have unique properties (thin and fragile). Moreover, we discovered that IAPP speed up αS amyloid formation and, at some conditions, the two proteins make mixed amyloids with distinctive features. The latter result offers a possible explanation why type-2 diabetes patients are pre-disposed for Parkinson's disease.