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

Autor: Jeremy Macedo, Stuart T Perry, Elissa Keogh, Xinyi Li, Adrian Apetri, Trevin Holland, Frederique Bard, Jaap Goudsmit, Julie Kim, Jeroen J.M. Hoozemans, Berdien Siregar, Martha Costa, Wouter Koudstaal, Lauren Fletcher, Gabriel Pascual, Hanna Inganäs, Margot van Winsen
Přispěvatelé: Pathology, Amsterdam Neuroscience - Neurodegeneration, Academic Medical Center
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Zdroj: Li, X, Koudstaal, W, Fletcher, L, Costa, M, van Winsen, M, Siregar, B, Inganäs, H, Kim, J, Keogh, E, Macedo, J, Holland, T, Perry, S, Bard, F, Hoozemans, J J, Goudsmit, J, Apetri, A & Pascual, G 2019, ' Naturally occurring antibodies isolated from PD patients inhibit synuclein seeding in vitro and recognize Lewy pathology ', Acta Neuropathologica, vol. 137, no. 5, pp. 825-836 . https://doi.org/10.1007/s00401-019-01974-5
Acta Neuropathologica
Acta Neuropathologica, 137(5), 825-836. Springer Verlag
Acta neuropathologica, 137(5), 825-836. Springer Verlag
ISSN: 0001-6322
DOI: 10.1007/s00401-019-01974-5
Popis: 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. Electronic supplementary material The online version of this article (10.1007/s00401-019-01974-5) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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