Targeting α-synuclein oligomers by protein-fragment complementation for drug discovery in synucleinopathies

Expert Opinion on Therapeutic Targets
Simon MoussaudPamela J McLean

Abstract

Reducing the burden of α-synuclein oligomeric species represents a promising approach for disease-modifying therapies against synucleinopathies such as Parkinson's disease and dementia with Lewy bodies. However, the lack of efficient drug discovery strategies that specifically target α-synuclein oligomers has been a limitation to drug discovery programs. Here we describe an innovative strategy that harnesses the power of bimolecular protein-fragment complementation to monitor synuclein-synuclein interactions. We have developed two robust models to monitor α-synuclein oligomerization by generating novel stable cell lines expressing α-synuclein fusion proteins for either fluorescent or bioluminescent protein-fragment complementation under the tetracycline-controlled transcriptional activation system. A pilot screen was performed resulting in the identification of two potential hits, a p38 MAPK inhibitor and a casein kinase 2 inhibitor, thereby demonstrating the suitability of our protein-fragment complementation assay for the measurement of α-synuclein oligomerization in living cells at high throughput. The application of the strategy described herein to monitor α-synuclein oligomer formation in living cells with high throughput ...Continue Reading

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Citations

Nov 19, 2015·Acta Neuropathologica·Corinna BliederhaeuserKarin M Danzer
Feb 3, 2016·Frontiers in Neuroscience·Marion DelenclosPamela J McLean
Jul 28, 2016·Proceedings of the National Academy of Sciences of the United States of America·Timothy S JarvelaIris Lindberg
Dec 27, 2018·Photochemistry and Photobiology·Svetlana V MarkovaEugene S Vysotski
Jul 3, 2019·Journal of Neurochemistry·Marion DelenclosPamela J McLean
Jan 15, 2020·Molecular Neurodegeneration·Jae-Hyeon ParkPamela J McLean
Apr 21, 2017·Frontiers in Neuroscience·Marion DelenclosPamela J McLean
Jun 30, 2021·NPJ Parkinson's Disease·Anthony R BraunJonathan N Sachs

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