Fibrillar form of α-synuclein-specific scFv antibody inhibits α-synuclein seeds induced aggregation and toxicity

• Published in: Scientific reports Vol. 10; no. 1; p. 8137
• Main Authors: Gupta, Vijay, Salim, Safa, Hmila, Issam, Vaikath, Nishant N., Sudhakaran, Indulekha P., Ghanem, Simona S., Majbour, Nour K., Abdulla, Sara A., Emara, Mohamed M., Abdesselem, Houari B., Lukacsovich, Tamas, Erskine, Daniel, El-Agnaf, Omar M. A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.05.2020; Nature Publishing Group
• Subjects: 14/1; 14/63; 692/699/375/1718; 692/699/375/365/1718; 82/16; 82/29; 82/51; 82/80; 82/83; alpha-Synuclein - chemistry; alpha-Synuclein - genetics; alpha-Synuclein - metabolism; alpha-Synuclein - toxicity; Atrophy; Autopsy; Blood-brain barrier; Brain - metabolism; Dementia disorders; Fibrils; Humanities and Social Sciences; Humans; Immunotherapy; Lewy bodies; Lewy body disease; Lewy Body Disease - genetics; Lewy Body Disease - metabolism; Monomers; Movement disorders; multidisciplinary; Neurodegenerative diseases; Neuroimaging; Neurotoxicity; Parkinson Disease - genetics; Parkinson Disease - metabolism; Parkinson's disease; Protein Aggregates; Protein Binding; Science; Science (multidisciplinary); Seeds; Single-Chain Antibodies - chemistry; Single-Chain Antibodies - genetics; Single-Chain Antibodies - metabolism; Synuclein; Toxicity
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-65035-8

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.