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Pharmacological inhibition of α-synuclein aggregation within liquid condensates

Accepted version
Peer-reviewed

Type

Article

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Authors

Dada, ST 
Toprakcioglu, Zenon 
Cali, Mariana P 
Rӧntgen, Alexander 
Hardenberg, Maarten C 

Abstract

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.

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Keywords

Journal Title

Nature Communications

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

Publisher

Nature Portfolio
Sponsorship
Horizon Europe UKRI Underwrite Innovate (10059436)
Horizon Europe UKRI Underwrite Innovate (10061100)
UKRI 10059436 and 10061100