Peptidomimetics Inspired by α-Synuclein or Its Chaperone αB-Crystallin Differentially Modulate α-Synuclein Aggregation

Aggregation of the α-Synuclein (αSyn) protein in neurons is responsible for synucleinopathies such as Parkinson’s disease. In healthy cells, αSyn is primarily present as monomers. Under pathological conditions, oligomers and fibrils are formed, leading to neuronal toxicity and death. No treatment prevents fatal synucleinopathies. We designed small peptidomimetics based on the structure of αSyn aggregates and on its chaperone protein αB-Crystallin. Interestingly, a relationship between the impact of peptidomimetics on the αSyn aggregation process, their sequences, and secondary conformation has been evidenced. In vitro and in cellular assays demonstrated that one compound based on αB-Crystallin was able to interfere with αSyn folding and aggregation by reducing the formation of oligomers and promoting off-pathway aggregation. The demonstration that physiological chaperone proteins can be mimicked by small peptide derivatives paves the way for new strategies to design inhibitors of amyloid protein aggregation, a hallmark of around 50 neurodegenerative and systemic amyloid diseases.