Modulation of α-synuclein fibrillization by ring-fused 2-pyridones: Templation and inhibition involve oligomers with different structure

• Published in: Archives of biochemistry and biophysics 2013-04, Vol.532 (2), p.84-90
• Main Authors: Horvath, Istvan, Sellstedt, Magnus, Weise, Christoph, Nordvall, Lina-Maria, Krishna Prasad, G., Olofsson, Anders, Larsson, Göran, Almqvist, Fredrik, Wittung-Stafshede, Pernilla
• Format: Article
• Language: English
• Subjects: 2-Pyridone; alpha-Synuclein - chemistry; alpha-Synuclein - metabolism; alpha-Synuclein - ultrastructure; Amyloid; Amyloid - antagonists & inhibitors; Amyloid - chemistry; Amyloid - metabolism; Amyloid - ultrastructure; Antiparkinson Agents - chemistry; Antiparkinson Agents - pharmacology; Humans; Oligomer; Parkinson Disease - drug therapy; Parkinson Disease - metabolism; Protein aggregation; Protein Structure, Secondary; Pyridones - chemistry; Pyridones - pharmacology; Spectroscopy; α-Synuclein
• ISSN: 0003-9861; 1096-0384; 1096-0384
• DOI: 10.1016/j.abb.2013.01.012

[Display omitted] ► 2-Pyridone compounds trigger formation of α-synuclein oligomers. ► The induced oligomers can either template or inhibit α-synuclein fibrillization. ► The two types of oligomer differ in secondary structure content. ► These compounds may be useful tools for mechanistic studies of fibrillization. In a recent study we discovered that a ring-fused 2-pyridone compound triggered fibrillization of a key protein in Parkinson’s disease, α-synuclein. To reveal how variations in compound structure affect protein aggregation, we now prepared a number of strategic analogs and tested their effects on α-synuclein amyloid fiber formation in vitro. We find that, in contrast to the earlier templating effect, some analogs inhibit α-synuclein fibrillization. For both templating and inhibiting compounds, the key species formed in the reactions are α-synuclein oligomers that contain compound. Despite similar macroscopic appearance, the templating and inhibiting oligomers are distinctly different in secondary structure content. When the inhibitory oligomers are added in seed amounts, they inhibit fresh α-synuclein aggregation reactions. Our study demonstrates that small chemical changes to the same central fragment can result in opposite effects on protein aggregation.