Specific inhibition of α-synuclein oligomer generation and toxicity by the chaperone domain Bri2 BRICHOS

Understanding the molecular mechanisms of neurodegenerative diseases and finding efficient treatments have been major priorities for research and society, yet new therapeutic approaches remain essential to face the socio-economic burden caused by these devastating diseases. Protein misfolding and aggregation are involved in several neurodegenerative disorders, such as α-synuclein (αSyn) implicated in Parkinson's disease. Elucidating the microscopic nucleation mechanisms has opened new opportunities to develop therapeutics against toxic mechanisms and species. Here, we show that naturally occurring molecular chaperones, represented by the anti-amyloid Bri2 BRICHOS domain, can be used to target αSyn-associated nucleation processes and structural species related to neurotoxicity. Our findings revealed that BRICHOS predominately suppresses the formation of new nucleation units on the fibrils surface (secondary nucleation), in addition to fibril-end elongation. This mechanism implies a drastic decrease of the oligomer generation rate. Besides targeting secondary nucleation sites on the fibril surface, BRICHOS directly binds to oligomeric αSyn species. Further, using ex vivo experiments, BRICHOS effectively diminishes αSyn fibril-related toxicity to hippocampal electrophysiology. Our studies show that molecular chaperones can be utilized as tools to target molecular processes and structural species related to αSyn neurotoxicity and have the potential as protein-based treatments against neurodegenerative disorders. ### Competing Interest Statement The authors have declared no competing interest.