Nanobodies raised against monomeric ɑ-synuclein inhibit fibril formation and destabilize toxic oligomeric species
| Autor: | Klenerman, D, Iljina, M, Hong, L, Horrocks, Mathew, Ludtmann, MH, Choi, ML, Hughes, Craig, Ruggeri, Francesco, Guilliams, T, Buell, AK, Lee, Ji-Eun, Gandhi, S, Lee, Steven, Bryant, Clare, Vendruscolo, Michele, Knowles, Tuomas, Dobson, Christopher, De Genst, E, Klenerman, David |
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| Přispěvatelé: | Ruggeri, Francesco [0000-0002-1232-1907], Lee, Steven [0000-0003-4492-5139], Bryant, Clare [0000-0002-2924-0038], Vendruscolo, Michele [0000-0002-3616-1610], Knowles, Tuomas [0000-0002-7879-0140], Klenerman, David [0000-0001-7116-6954], Apollo - University of Cambridge Repository |
| Rok vydání: | 2017 |
| Předmět: | |
| Popis: | $\textbf{Background:}$ The aggregation of the protein ɑ-synuclein (ɑS) 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 ɑS, although a detailed molecular-level mechanism of the action of such species remains elusive. Here, we characterize ɑS aggregation in vitro in the presence of two ɑS-specific single-domain antibodies (nanobodies), NbSyn2 and NbSyn87, which bind to the highly accessible C-terminal region of ɑS. $\textbf{Results:}$ We show that both nanobodies inhibit the formation of ɑS 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 ɑS, leading to a dramatic reduction in oligomer-induced cellular toxicity. $\textbf{Conclusions:}$ 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. Parkinson’s UK (H-0903). EDG was supported by the Medical Research Council (MRC G1002272). DK was funded by ERC (669237) and the Royal Society. |
| Databáze: | OpenAIRE |
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