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Small‐Molecule‐Induced Soluble Oligomers of α‐Synuclein with Helical Structure
Author(s) -
FonsecaOrnelas Luis,
Schmidt Carla,
CamachoZarco Aldo R.,
Fernandez Claudio O.,
Becker Stefan,
Zweckstetter Markus
Publication year - 2017
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201703001
Subject(s) - synucleinopathies , monomer , oligomer , chemistry , phthalocyanine , molecule , intermolecular force , biophysics , sequence (biology) , alpha synuclein , biochemistry , polymer , biology , parkinson's disease , polymer chemistry , organic chemistry , disease , medicine , pathology
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.