title: Modulation of α-synuclein fibrillization by ring-fused 2-pyridones: templation and inhibition involve oligomers with different structure.
abstract: 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.
authors: Department of Chemistry, Umeå University, 901 87 Umeå, Sweden.
authors: Istvan
authors: I
authors: Horvath
authors: Magnus
authors: M
authors: Sellstedt
authors: Christoph
authors: C
authors: Weise
authors: Lina-Maria
authors: LM
authors: Nordvall
authors: G
authors: G
authors: Krishna Prasad
authors: Anders
authors: A
authors: Olofsson
authors: Göran
authors: G
authors: Larsson
authors: Fredrik
authors: F
authors: Almqvist
authors: Pernilla
authors: P
authors: Wittung-Stafshede
mesh_terms: D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D000978:Antiparkinson Agents / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism; D017433:Protein Structure, Secondary; D011728:Pyridones / Q000737:chemistry* / Q000494:pharmacology*; D051844:alpha-Synuclein / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D000682:Amyloid; D000978:Antiparkinson Agents; D011728:Pyridones; D051844:alpha-Synuclein; C017679:2-hydroxypyridine