An approach to characterize mechanisms of action of anti-amyloidogenic compounds in vitro and in situ
Amyloid aggregation is associated with neurodegenerative disease and its modulation is a focus of drug development. We developed a chemical proteomics pipeline to probe the mechanism of action of anti-amyloidogenic compounds. Our approach identifies putative interaction sites with high resolution, can probe compound interactions with specific target conformations and directly in cell and brain extracts, and identifies off-targets. We analysed interactions of six anti-amyloidogenic compounds and the amyloid binder Thioflavin T with different conformations of the Parkinson's disease protein α-Synuclein and tested specific compounds in cell or brain lysates. AC Immune compound 2 interacted with α-Synuclein in vitro, in intact neurons and in neuronal lysates, reduced neuronal α-Synuclein levels in a seeded model, and had protective effects. EGCG, Baicalein, ThT and doxycycline interacted with α-Synuclein in vitro but not substantially in cell lysates, with many additional putative targets, underscoring the importance of testing compounds in situ. Our pipeline will enable screening of compounds against any amyloidogenic proteins in cell and patient brain extracts and mechanistic studies of compound action.
Authors
- Yanick Fleischmann (ORCID: https://orcid.org/0000-0002-5629-295X)
- Patrick Stalder (ORCID: https://orcid.org/0000-0003-4005-8488)
- L. Malinovska
- Nadine Ait‐Bouziad (ORCID: https://orcid.org/0000-0003-3182-4179)
- Jan Stöhr
- Jan-Philipp Quast (ORCID: https://orcid.org/0000-0003-2713-778X)
- Cédric Boudou (ORCID: https://orcid.org/0000-0001-7230-2380)
- Tetiana Serdiuk (ORCID: https://orcid.org/0000-0002-3706-5911)
- Nicolas R. de Souza (ORCID: https://orcid.org/0000-0003-4099-9544)
- Dhiman Ghosh (ORCID: https://orcid.org/0000-0003-2087-8075)
- Aurélien Davranche
- Walther Hänseler (ORCID: https://orcid.org/0000-0003-4868-3704)
- Elpida Tsika (ORCID: https://orcid.org/0000-0003-4189-4234)
- Roland Riek (ORCID: https://orcid.org/0000-0002-6333-066X)
- Ronald Melki (ORCID: https://orcid.org/0000-0003-0000-7096)
- Paola Picotti (ORCID: https://orcid.org/0000-0002-4109-3552)
- A. Ouared
Institutions
- University of Geneva (CH)
- Centre National de la Recherche Scientifique (FR)
- University of Zurich (CH)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- AbbVie (United States) (US)
- ETH Zurich (CH)
- AC Immune (Switzerland) (CH)
- CEA Paris-Saclay - Etablissement de Fontenay-aux-roses (FR)
- Direction de la Recherche Fondamentale (FR)
- Discovery Laboratories (United States) (US)
- École Polytechnique Fédérale de Lausanne (CH)
Publication Details
- Journal
- npj Parkinson s Disease
- Published
- 2025-05-10
- DOI
- https://doi.org/10.1038/s41531-025-00966-5
- Citations
- 6
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 6.99
Funders
- National Science Foundation
- Imperial College London
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Eidgenössische Technische Hochschule Zürich
- ETH Zürich Foundation
- Parkinson Schweiz