High-throughput screening methodology to identify alpha-synuclein aggregation inhibitors

Jordi Pujols, Samuel Peña-Díaz, María Conde-Giménez, Francisca Pinheiro, Susanna Navarro, Javier Sancho, Salvador Ventura

Research output: Contribution to journalArticleResearchpeer-review

26 Citations (Scopus)

Abstract

© 2017 by the authors. Licensee MDPI, Basel, Switzerland. An increasing number of neurodegenerative diseases are being found to be associated with the abnormal accumulation of aggregated proteins in the brain. In Parkinson’s disease, this process involves the aggregation of alpha-synuclein (α-syn) into intraneuronal inclusions. Thus, compounds that inhibit α-syn aggregation represent a promising therapeutic strategy as disease-modifying agents for neurodegeneration. The formation of α-syn amyloid aggregates can be reproduced in vitro by incubation of the recombinant protein. However, the in vitro aggregation of α-syn is exceedingly slow and highly irreproducible, therefore precluding fast high throughput anti-aggregation drug screening. Here, we present a simple and easy-to-implement in-plate method for screening large chemical libraries in the search for α-syn aggregation modulators. It allows us to monitor aggregation kinetics with high reproducibility, while being faster and requiring lower protein amounts than conventional aggregation assays. We illustrate how the approach enables the identification of strong aggregation inhibitors in a library of more than 14,000 compounds.
Original languageEnglish
Article number478
JournalInternational Journal of Molecular Sciences
Volume18
Issue number3
DOIs
Publication statusPublished - 1 Mar 2017

Keywords

  • Amyloid
  • High-throughput screening
  • Parkinson disease
  • Protein aggregation
  • α-synuclein

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