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Binding Stability of Antibody—α-Synuclein Complexes Predicts the Protective Efficacy of Anti-α-synuclein Antibodies

Spreading of alpha-synuclein (αSyn) may play an important role in Parkinson’s disease and related synucleinopathies. Passive immunization with anti-αSyn antibodies is a promising method to slow down the spreading process and thereby the progression of synucleinopathies. Currently, it remains elusive...

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Autores principales: Höllerhage, Matthias, Wolff, Andreas, Chakroun, Tasnim, Evsyukov, Valentin, Duan, Linghan, Chua, Oscar Wing-Ho, Tang, Qilin, Koeglsperger, Thomas, Höglinger, Günter U.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9167191/
https://www.ncbi.nlm.nih.gov/pubmed/35460053
http://dx.doi.org/10.1007/s12035-022-02824-4
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author Höllerhage, Matthias
Wolff, Andreas
Chakroun, Tasnim
Evsyukov, Valentin
Duan, Linghan
Chua, Oscar Wing-Ho
Tang, Qilin
Koeglsperger, Thomas
Höglinger, Günter U.
author_facet Höllerhage, Matthias
Wolff, Andreas
Chakroun, Tasnim
Evsyukov, Valentin
Duan, Linghan
Chua, Oscar Wing-Ho
Tang, Qilin
Koeglsperger, Thomas
Höglinger, Günter U.
author_sort Höllerhage, Matthias
collection PubMed
description Spreading of alpha-synuclein (αSyn) may play an important role in Parkinson’s disease and related synucleinopathies. Passive immunization with anti-αSyn antibodies is a promising method to slow down the spreading process and thereby the progression of synucleinopathies. Currently, it remains elusive which specific characteristics are essential to render therapeutic antibodies efficacious. Here, we established a neuronal co-culture model, in which αSyn species are being released from αSyn-overexpressing cells and induce toxicity in a priori healthy GFP-expressing cells. In this model, we investigated the protective efficacy of three anti-αSyn antibodies. Only two of these antibodies, one C-terminal and one N-terminal, protected from αSyn-induced toxicity by inhibiting the uptake of spreading-competent αSyn from the cell culture medium. Neither the binding epitope nor the affinity of the antibodies towards recombinant αSyn could explain differences in biological efficacy. However, both protective antibodies formed more stable antibody-αSyn complexes than the non-protective antibody. These findings indicate that the stability of antibody-αSyn complexes may be more important to confer protection than the binding epitope or affinity to recombinant αSyn.
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spelling pubmed-91671912022-06-06 Binding Stability of Antibody—α-Synuclein Complexes Predicts the Protective Efficacy of Anti-α-synuclein Antibodies Höllerhage, Matthias Wolff, Andreas Chakroun, Tasnim Evsyukov, Valentin Duan, Linghan Chua, Oscar Wing-Ho Tang, Qilin Koeglsperger, Thomas Höglinger, Günter U. Mol Neurobiol Article Spreading of alpha-synuclein (αSyn) may play an important role in Parkinson’s disease and related synucleinopathies. Passive immunization with anti-αSyn antibodies is a promising method to slow down the spreading process and thereby the progression of synucleinopathies. Currently, it remains elusive which specific characteristics are essential to render therapeutic antibodies efficacious. Here, we established a neuronal co-culture model, in which αSyn species are being released from αSyn-overexpressing cells and induce toxicity in a priori healthy GFP-expressing cells. In this model, we investigated the protective efficacy of three anti-αSyn antibodies. Only two of these antibodies, one C-terminal and one N-terminal, protected from αSyn-induced toxicity by inhibiting the uptake of spreading-competent αSyn from the cell culture medium. Neither the binding epitope nor the affinity of the antibodies towards recombinant αSyn could explain differences in biological efficacy. However, both protective antibodies formed more stable antibody-αSyn complexes than the non-protective antibody. These findings indicate that the stability of antibody-αSyn complexes may be more important to confer protection than the binding epitope or affinity to recombinant αSyn. Springer US 2022-04-22 2022 /pmc/articles/PMC9167191/ /pubmed/35460053 http://dx.doi.org/10.1007/s12035-022-02824-4 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Höllerhage, Matthias
Wolff, Andreas
Chakroun, Tasnim
Evsyukov, Valentin
Duan, Linghan
Chua, Oscar Wing-Ho
Tang, Qilin
Koeglsperger, Thomas
Höglinger, Günter U.
Binding Stability of Antibody—α-Synuclein Complexes Predicts the Protective Efficacy of Anti-α-synuclein Antibodies
title Binding Stability of Antibody—α-Synuclein Complexes Predicts the Protective Efficacy of Anti-α-synuclein Antibodies
title_full Binding Stability of Antibody—α-Synuclein Complexes Predicts the Protective Efficacy of Anti-α-synuclein Antibodies
title_fullStr Binding Stability of Antibody—α-Synuclein Complexes Predicts the Protective Efficacy of Anti-α-synuclein Antibodies
title_full_unstemmed Binding Stability of Antibody—α-Synuclein Complexes Predicts the Protective Efficacy of Anti-α-synuclein Antibodies
title_short Binding Stability of Antibody—α-Synuclein Complexes Predicts the Protective Efficacy of Anti-α-synuclein Antibodies
title_sort binding stability of antibody—α-synuclein complexes predicts the protective efficacy of anti-α-synuclein antibodies
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9167191/
https://www.ncbi.nlm.nih.gov/pubmed/35460053
http://dx.doi.org/10.1007/s12035-022-02824-4
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