Pharmacological inhibition of α-synuclein aggregation within liquid condensates

Samuel T. Dada, Zenon Toprakcioglu, Mariana P. Cali, Alexander Röntgen, Maarten C. Hardenberg, Owen M. Morris, Lena K. Mrugalla, Tuomas P. J. Knowles and Michele Vendruscolo ()
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Samuel T. Dada: University of Cambridge
Zenon Toprakcioglu: University of Cambridge
Mariana P. Cali: University of Cambridge
Alexander Röntgen: University of Cambridge
Maarten C. Hardenberg: University of Cambridge
Owen M. Morris: University of Cambridge
Lena K. Mrugalla: University of Cambridge
Tuomas P. J. Knowles: University of Cambridge
Michele Vendruscolo: University of Cambridge

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47585-x

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