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

Simon Moussaud, Siobhan Malany, Alka Mehta, Stefan Vasile, Layton H. Smith, Pamela J McLean

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Objective: 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.Research design and methods: 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.Main outcome measures: 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.Conclusions: The application of the strategy described herein to monitor α-synuclein oligomer formation in living cells with high throughput will facilitate drug discovery efforts for disease-modifying therapies against synucleinopathies and other proteinopathies.

Original languageEnglish (US)
Pages (from-to)589-603
Number of pages15
JournalExpert Opinion on Therapeutic Targets
Volume19
Issue number5
DOIs
StatePublished - May 1 2015

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Keywords

  • High-throughput screening
  • Oligomers
  • Parkinson's disease
  • Protein-fragment complementation
  • Synucleinopathy
  • α-synuclein

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmacology
  • Clinical Biochemistry
  • Molecular Medicine

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