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

13 Citations (Scopus)

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

Fingerprint

Synucleins
Drug Discovery
Oligomers
Proteins
Oligomerization
Cells
Luminescent Proteins
Throughput
Casein Kinase II
Lewy Body Disease
p38 Mitogen-Activated Protein Kinases
Tetracycline
Transcriptional Activation
Parkinson Disease
Assays
Research Design
Fusion reactions
Chemical activation
Outcome Assessment (Health Care)
Cell Line

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

Cite this

Targeting α-synuclein oligomers by protein-fragment complementation for drug discovery in synucleinopathies. / Moussaud, Simon; Malany, Siobhan; Mehta, Alka; Vasile, Stefan; Smith, Layton H.; McLean, Pamela J.

In: Expert Opinion on Therapeutic Targets, Vol. 19, No. 5, 01.05.2015, p. 589-603.

Research output: Contribution to journalArticle

Moussaud, Simon ; Malany, Siobhan ; Mehta, Alka ; Vasile, Stefan ; Smith, Layton H. ; McLean, Pamela J. / Targeting α-synuclein oligomers by protein-fragment complementation for drug discovery in synucleinopathies. In: Expert Opinion on Therapeutic Targets. 2015 ; Vol. 19, No. 5. pp. 589-603.
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