RESUMEN
The deposition of the amyloid-ß (Aß) peptide into amyloid fibrils is a hallmark of Alzheimer's disease. Recently, it has been reported that some proteins can aggregate and form amyloids through an intermediate pathway involving a liquid-like condensed phase. These observations prompted us to investigate the phase space of Aß. We thus explored the ability of Aß to undergo liquid-liquid phase separation, and the subsequent liquid-to-solid transition that takes place within the resulting condensates. Through the use of microfluidic approaches, we observed that the 40-residue form of Αß (Αß40) can undergo liquid-liquid phase separation, and that accessing a liquid-like intermediate state enables Αß40 to self-assemble and aggregate into amyloid fibrils through this pathway. These results prompt further studies to investigate the possible role of Αß liquid-liquid phase separation and its subsequent aggregation in the context of Alzheimer's disease and more generally on neurodegenerative processes.
Asunto(s)
Péptidos beta-Amiloides , Péptidos beta-Amiloides/química , Péptidos beta-Amiloides/metabolismo , Humanos , Fragmentos de Péptidos/química , Fragmentos de Péptidos/metabolismo , Transición de Fase , Agregado de Proteínas , Enfermedad de Alzheimer/metabolismo , Amiloide/química , Amiloide/metabolismo , Agregación Patológica de Proteínas/metabolismo , Extracción Líquido-Líquido/métodos , Separación de FasesRESUMEN
Aggregated forms of α-synuclein constitute the major component of Lewy bodies, the proteinaceous aggregates characteristic of Parkinson's disease. Emerging evidence suggests that α-synuclein aggregation may occur within liquid condensates formed through phase separation. This mechanism of aggregation creates new challenges and opportunities for drug discovery for Parkinson's disease, which is otherwise still incurable. Here we show that the condensation-driven aggregation pathway of α-synuclein can be inhibited using small molecules. We report that the aminosterol claramine stabilizes α-synuclein condensates and inhibits α-synuclein aggregation within the condensates both in vitro and in a Caenorhabditis elegans model of Parkinson's disease. By using a chemical kinetics approach, we show that the mechanism of action of claramine is to inhibit primary nucleation within the condensates. These results illustrate a possible therapeutic route based on the inhibition of protein aggregation within condensates, a phenomenon likely to be relevant in other neurodegenerative disorders.
