Nanobodies raised against monomeric ?-synuclein inhibit fibril formation and destabilize toxic oligomeric species.

ABSTRACT:

Background

The aggregation of the protein ?-synuclein (?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 ?S, although a detailed molecular-level mechanism of the action of such species remains elusive. Here, we characterize ?S aggregation in vitro in the presence of two ?S-specific single-domain antibodies (nanobodies), NbSyn2 and NbSyn87, which bind to the highly accessible C-terminal region of ?S.

Results

We show that both nanobodies inhibit the formation of ?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 ?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.

SUBMITTER: Iljina M 

PROVIDER: S-EPMC5496350 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature