Fibrillar form of α-synuclein-specific scFv antibody inhibits α-synuclein seeds induced aggregation and toxicity.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
18 05 2020
18 05 2020
Historique:
received:
19
07
2019
accepted:
24
04
2020
entrez:
20
5
2020
pubmed:
20
5
2020
medline:
15
12
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32424162
doi: 10.1038/s41598-020-65035-8
pii: 10.1038/s41598-020-65035-8
pmc: PMC7235225
doi:
Substances chimiques
Protein Aggregates
0
Single-Chain Antibodies
0
alpha-Synuclein
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
8137Subventions
Organisme : Medical Research Council
ID : G0400074
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0502157
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0900652
Pays : United Kingdom
Organisme : Medical Research Council
ID : G1100540
Pays : United Kingdom
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