Small molecule-induced soluble oligomers of α-synuclein with helical structure.

Accumulation of alpha-synuclein (alpha Syn) aggregates constitutes the hallmark of synucleinopathies including Parkinson's disease. However, many steps from the innocuous, monomeric alpha Syn toward misfolded oligomers and fibrillar species remain unclear. Here, we show that alpha Syn can form in solution alpha-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 alpha Syn sequence in the phthalocyanine tetrasulfonate-stabilized alpha Syn oligomers. Our study suggests that stabilization of structured oligomers by small molecules provides a viable strategy to interfere with alpha Syn fibrillization.