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.