Nanobodies raised against monomeric α-synuclein inhibit fibril formation and destabilize toxic oligomeric species

Marija Iljina, Liu Hong, Mathew H. Horrocks, Marthe H. Ludtmann, Minee L. Choi, Craig D. Hughes, Francesco S. Ruggeri, Tim Guilliams, Alexander K. Buell, Ji Eun Lee, Sonia Gandhi, Steven F. Lee, Clare E. Bryant, Michele Vendruscolo, Tuomas P.J. Knowles, Christopher M. Dobson*, Erwin De Genst, David Klenerman

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

56 Citations (Scopus)

Abstract

Background: The aggregation of the protein α-synuclein (αS) underlies a range of increasingly common neurodegenerative disorders including Parkinson's disease. One widely explored therapeutic strategy for these conditions is the use of antibodies to target aggregated αS, although a detailed molecular-level mechanism of the action of such species remains elusive. Here, we characterize αS aggregation in vitro in the presence of two αS-specific single-domain antibodies (nanobodies), NbSyn2 and NbSyn87, which bind to the highly accessible C-terminal region of αS. Results: We show that both nanobodies inhibit the formation of αS fibrils. Furthermore, using single-molecule fluorescence techniques, we demonstrate that nanobody binding promotes a rapid conformational conversion from more stable oligomers to less stable oligomers of αS, leading to a dramatic reduction in oligomer-induced cellular toxicity. Conclusions: The results indicate a novel mechanism by which diseases associated with protein aggregation can be inhibited, and suggest that NbSyn2 and NbSyn87 could have significant therapeutic potential.
Original languageEnglish
Article number57
JournalBMC Biology
Volume15
Issue number1
DOIs
Publication statusPublished - 3 Jul 2017
Externally publishedYes

Keywords

  • Aggregation inhibitors
  • Amyloid toxicity
  • Antibody
  • Neurodegeneration
  • Protein aggregation
  • Single-molecule fluorescence

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