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Open Access 01-05-2019 | Pathology | Original Paper

Naturally occurring antibodies isolated from PD patients inhibit synuclein seeding in vitro and recognize Lewy pathology

Authors: Xinyi Li, Wouter Koudstaal, Lauren Fletcher, Martha Costa, Margot van Winsen, Berdien Siregar, Hanna Inganäs, Julie Kim, Elissa Keogh, Jeremy Macedo, Trevin Holland, Stuart Perry, Frederique Bard, Jeroen J. Hoozemans, Jaap Goudsmit, Adrian Apetri, Gabriel Pascual

Published in: Acta Neuropathologica | Issue 5/2019

Abstract

Deposition of α-synuclein into Lewy bodies and Lewy neurites is the hallmark of Parkinson’s disease (PD). It is hypothesized that α-synuclein pathology spreads by a “prion-like” mechanism (i.e., by seeded aggregation or templated misfolding). Therefore, various extracellular α-synuclein conformers and/or posttranslational modifications may serve as biomarkers of disease or potential targets for novel interventions. To explore whether the antibody repertoires of PD patients contain anti-α-synuclein antibodies that can potentially be used as markers or immunotherapy, we interrogated peripheral IgG⁺ memory B cells from PD patients for reactivity to α-synuclein. In total, ten somatically mutated antibodies were recovered, suggesting the presence of an ongoing antigen-driven immune response. The three antibodies that had the highest affinity to recombinant full-length α-synuclein, aSyn-323.1, aSyn-336.1 and aSyn-338.1, were characterized further and shown to recognize epitopes in the C terminus of α-synuclein with binding affinities between 0.3 and 2.8 μM. Furthermore, all three antibodies were able to neutralize the “seeding” of intracellular synuclein aggregates in an in vitro α-synuclein seeding assay. Finally, differential reactivities were observed for all three human anti-α-synuclein antibodies across tissue treatment conditions by immunohistochemistry. Our results suggest that the memory B-cell repertoire of PD patients might represent a potential source of biomarkers and therapies.

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Title: Naturally occurring antibodies isolated from PD patients inhibit synuclein seeding in vitro and recognize Lewy pathology
Authors: Xinyi Li
Wouter Koudstaal
Lauren Fletcher
Martha Costa
Margot van Winsen
Berdien Siregar
Hanna Inganäs
Julie Kim
Elissa Keogh
Jeremy Macedo
Trevin Holland
Stuart Perry
Frederique Bard
Jeroen J. Hoozemans
Jaap Goudsmit
Adrian Apetri
Gabriel Pascual
Publication date: 01-05-2019
Publisher: Springer Berlin Heidelberg
Keywords: Pathology
Parkinson's Disease
Published in: Acta Neuropathologica / Issue 5/2019
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-019-01974-5

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Naturally occurring antibodies isolated from PD patients inhibit synuclein seeding in vitro and recognize Lewy pathology

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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