Academic Journal
Nanobodies raised against monomeric ɑ-synuclein inhibit fibril formation and destabilize toxic oligomeric species
| العنوان: | Nanobodies raised against monomeric ɑ-synuclein inhibit fibril formation and destabilize toxic oligomeric species |
|---|---|
| المؤلفون: | 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 |
| بيانات النشر: | BioMed Central BMC Biology |
| سنة النشر: | 2017 |
| المجموعة: | Apollo - University of Cambridge Repository |
| مصطلحات موضوعية: | protein aggregation, amyloid toxicity, neurodegeneration, aggregation inhibitors, antibody, single-molecule fluorescence |
| الوصف: | $\textbf{Background:}$ 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. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf; application/vnd.openxmlformats-officedocument.wordprocessingml.document |
| اللغة: | English |
| Relation: | https://www.repository.cam.ac.uk/handle/1810/264943 |
| DOI: | 10.17863/CAM.10303 |
| الاتاحة: | https://doi.org/10.17863/CAM.10303 https://www.repository.cam.ac.uk/handle/1810/264943 |
| Rights: | Attribution 4.0 International ; http://creativecommons.org/licenses/by/4.0/ |
| رقم الانضمام: | edsbas.E2F3A70A |
| قاعدة البيانات: | BASE |
| DOI: | 10.17863/CAM.10303 |
|---|