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Lookup NU author(s): Dr Daniel Erskine
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Synucleinopathies including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) are characterized by pathological accumulation of α-synuclein (α-syn). Amongst the various approaches attempting to tackle the pathological features of synucleinopathies, antibody-based immunotherapy holds much promise. However, the large size of antibodies and corresponding difficulty in crossing the blood-brain barrier has limited development in this area. To overcome this issue, we engineered single-chain variable fragments (scFvs) against fibrillar α-syn, a putative disease-relevant form of α-syn. The purified scFvs showed specific activity towards α-syn fibrils and oligomers in comparison to monomers and recognized intracellular inclusions in human post-mortem brain tissue of Lewy body disease cases, but not aged controls. In vitro studies indicated scFvs inhibit the seeding of α-syn aggregation in a time-dependent manner, decreased α-syn seed-induced toxicity in a cell model of PD, and reduced the production of insoluble α-syn phosphorylated at Ser-129 (pS129-α-syn). These results suggest that our α-syn fibril-specific scFvs recognize α-syn pathology and can inhibit the aggregation of α-syn in vitro and prevent seeding-dependent toxicity. Therefore, the scFvs described here have considerable potential to be utilized towards immunotherapy in synucleinopathies and may also have applications in ante-mortem imaging modalities.
Author(s): Gupta V, Salim S, Hmila I, Vaikath NN, Sudhakaran IP, Ghanem SS, Majbour NK, Abdulla SA, Emara MM, Abdesselem HB, Lukacsovich T, Erskine D, El-Agnaf OMA
Publication type: Article
Publication status: Published
Journal: Scientific Reports
Print publication date: 18/05/2020
Online publication date: 18/05/2020
Acceptance date: 24/04/2020
Date deposited: 24/05/2020
ISSN (electronic): 2045-2322
Publisher: Nature Publishing Group
PubMed id: 32424162
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