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

ABSTRACT: Reducing the burden of ?-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 ?-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 ?-synuclein oligomerization by generating novel stable cell lines expressing ?-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 ?-synuclein oligomerization in living cells at high throughput.The application of the strategy described herein to monitor ?-synuclein oligomer formation in living cells with high throughput will facilitate drug discovery efforts for disease-modifying therapies against synucleinopathies and other proteinopathies.

SUBMITTER: Moussaud S 

PROVIDER: S-EPMC4608017 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature