期刊
BMC BIOLOGY
卷 15, 期 -, 页码 -出版社
BMC
DOI: 10.1186/s12915-017-0390-6
关键词
Protein aggregation; Amyloid toxicity; Neurodegeneration; Aggregation inhibitors; Antibody; Single-molecule fluorescence
类别
资金
- Dr Tayyeb Hussain Scholarship
- ERC [669237]
- China Scholarship Council
- NSFC [11204150]
- Parkinson's UK [H-0903]
- Medical Research Council (MRC) [G1002272]
- Royal Society
- Wellcome Trust
- Wellcome Trust [100172/Z/12/Z] Funding Source: Wellcome Trust
- MRC [G1002272] Funding Source: UKRI
- Alzheimers Research UK [ARUK-IRG2014-13] Funding Source: researchfish
- Medical Research Council [G1002272] Funding Source: researchfish
- Parkinson's UK [H-0903] Funding Source: researchfish
- Wellcome Trust [100172/Z/12/Z] Funding Source: researchfish
- European Research Council (ERC) [669237] Funding Source: European Research Council (ERC)
Background: The aggregation of the protein alpha-synuclein (alpha S) 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 alpha S, although a detailed molecular-level mechanism of the action of such species remains elusive. Here, we characterize alpha S aggregation in vitro in the presence of two alpha S-specific single-domain antibodies (nanobodies), NbSyn2 and NbSyn87, which bind to the highly accessible C-terminal region of alpha S. Results: We show that both nanobodies inhibit the formation of alpha S 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 alpha S, 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.
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