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 language | English |
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Article number | 57 |
Journal | BMC Biology |
Volume | 15 |
Issue number | 1 |
DOIs | |
Publication status | Published - 3 Jul 2017 |
Externally published | Yes |
Keywords
- Aggregation inhibitors
- Amyloid toxicity
- Antibody
- Neurodegeneration
- Protein aggregation
- Single-molecule fluorescence