Small-Molecule-Induced Soluble Oligomers of α-Synuclein with Helical Structure

FONSECA-ORNELAS, LUIS; SCHMIDT, CARLA; CAMACHO-ZARCO, ALDO R.; FERNANDEZ, CLAUDIO O.; BECKER, STEFAN; ZWECKSTETTER, MARKUS

CHEMISTRY-A EUROPEAN JOURNAL

WILEY-V C H VERLAG GMBH

Año: 2017 vol. 23 p. 13010 - 13014

0947-6539

Accumulation of α-synuclein (αSyn) aggregates constitutes the hallmark of synucleinopathies including Parkinson´s disease. However, many steps from the innocuous, monomeric αSyn toward misfolded oligomers and fibrillar species remain unclear. Here, we show that αSyn can form in solution α-helical oligomers, which are off-pathway to fibrillization, through interaction with the tetrapyrrole phthalocyanine tetrasulfonate. Chemical cross-linking combined with mass spectrometry reveals a large number of intermolecular cross-links along the entire αSyn sequence in the phthalocyanine tetrasulfonate-stabilized αSyn oligomers. Our study suggests that stabilization of structured oligomers by small molecules provides a viable strategy to interfere with αSyn fibrillization.