Iljina, M;
Hong, L;
Horrocks, MH;
Ludtmann, MH;
Choi, ML;
Hughes, CD;
Ruggeri, FS;
... Klenerman, D; + view all
(2017)
Nanobodies raised against monomeric alpha-synuclein inhibit fibril formation and destabilize toxic oligomeric species.
BMC Biology
, 15
, Article 57. 10.1186/s12915-017-0390-6.
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Abstract
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. 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. 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.
| Type: | Article |
|---|---|
| Title: | Nanobodies raised against monomeric alpha-synuclein inhibit fibril formation and destabilize toxic oligomeric species |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1186/s12915-017-0390-6 |
| Publisher version: | http://doi.org/10.1186/s12915-017-0390-6 |
| Language: | English |
| Additional information: | © Klenerman et al. 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Biology, Life Sciences & Biomedicine - Other Topics, Protein aggregation, Amyloid toxicity, Neurodegeneration, Aggregation inhibitors, Antibody, Single-molecule fluorescence, SINGLE-MOLECULE FLUORESCENCE, SPORADIC PARKINSONS-DISEASE, MULTIPLE SYSTEM ATROPHY, ANTIBODY FRAGMENTS, LEWY BODIES, AGGREGATION, NEURODEGENERATION, PATHOLOGY, BRAIN, IMMUNOREACTIVITY |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1565307 |
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