Synaptophysin autoantibodies mediate synaptic dysfunction in cerebellar ataxia.
Overview
22 affiliations
- Institute of Clinical Neuroimmunology, LMU University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany
- Biomedical Center, Medical Faculty, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
- Graduate School of Systemic Neuroscience, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
- Department of Translational Immunology, Department of Medicine 3 – Rheumatology and Immunology, Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, 91054 Erlangen, Germany
- German Center for Neurodegenerative Diseases, 53127 Bonn, Germany
- Center of Neurology, Department of Parkinson’s, Sleep and Movement Disorders, University Hospital Bonn, 53127 Bonn, Germany
- Children’s Hospital Datteln, Pediatric Neurology, Witten/Herdecke University, 45711 Datteln, Germany
- The Institute for Molecular Medicine, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA
- Translational Research Unit, Thoraxklinik at University Hospital Heidelberg, 69126 Heidelberg, Germany
- Translational Lung Research Center Heidelberg, German Center for Lung Research (DZL), 69126 Heidelberg, Germany
- Koç University Research Center for Translational Medicine (KUTTAM), İstanbul 34450, Türkiye
- Koç University Graduate School of Health Sciences, İstanbul 34450, Türkiye
- Koç University School of Medicine, Department of Neurology, İstanbul 34450, Türkiye
- Department of Neurology, Hospital Murtal, 8720 Knittelfeld, Austria
- Department of Neurology, Division of Neuropathology and Neurochemistry, Medical University of Vienna, 1090 Vienna, Austria
- Comprehensive Center for Clinical Neurosciences and Mental Health, Medical University of Vienna, 1090 Vienna, Austria
- Department of Neuroradiology, University Hospital Bonn, 53127 Bonn, Germany
- Friedrich-Baur-Institute at the Department of Neurology, LMU University Hospital, Ludwig-Maximilians-Universität München, 80336 Munich, Germany
- German Center for Neurodegenerative Diseases, 81377 Munich, Germany
- Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany
- Technology Platform Pluripotent Stem Cells, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, 91054 Erlangen, Germany
Abstract
Cerebellar ataxias (CAs) encompass a wide spectrum of genetic and sporadic origins, of which a portion is driven by immune-mediated pathomechanisms. While some patients harbor known autoantibodies, assisting diagnosis and treatment, many remain seronegative. Here, we identify synaptophysin (SYP) as an autoantigen in CA by serum IgG staining on primate tissue, combined with human protein array and cell-based assay (CBA). SYP is abundant in presynaptic vesicles and is transiently exposed on the cell surface. Out of 43 patients with CA with synaptic serum reactivity on cerebellar sections, SYP antibodies were identified by CBA in 2 patients. Exposure of human induced pluripotent stem cell (iPSC)-derived glutamatergic neurons to patient’s IgG with SYP antibodies causes selective SYP accumulation at the presynaptic membrane. Patient’s IgG and SYP monoclonal antibody reduce neuronal populational activity recorded by multi-electrode array. Altogether, we identify SYP as an autoantigen for further stratifying patients with CA. Our functional experiments with SYP antibodies uncover a previously unrecognized mechanism of antibody-mediated synaptic dysfunction.
Reproduced under the paper's license (CC BY), from the paper cited above.
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Data and code availability
The datasets generated and analyzed during this study are available from the corresponding author on reasonable request.
The data underlying quantification of intensities at MAP2+ pixels, representing presynapses proximal to dendrites in Figure 5, has been provided as a macroscript (supplemental information).
Any additional information required to reanalyze the data reported in this work is available from the lead contact upon request.
Reproduced under the paper's license (CC BY), from the paper cited above.
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Version 1, 28 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 21 authors, 6 keywords, 14 MeSH terms, 7 funders, 65 references, 16 RRIDs.
Cite
This paper
Ho, S., Wong, H. K., Shqau, D., Winklmeier, S., Grobe-Einsler, M., Rostasy, K., Kümpfel, T., Thaler, F. S., Brimberg, L., Schneider, M. A., Muley, T., Vural, A., Seifert-Held, T., Endmayr, V., Höftberger, R., Faber, J., Klopstock, T., Frahm, S., Gerdes, L. A., . . . Mader, S. (2026). Synaptophysin autoantibodies mediate synaptic dysfunction in cerebellar ataxia. Cell reports. Medicine, 7(6), 102822. https://
BibTeX
@article{ho2026synaptoph
author = {Ho, Samantha and Wong, Hoi Kiu and Shqau, Dorina and Winklmeier, Stephan and Grobe-Einsler, Marcus and Rostasy, Kevin and Kümpfel, Tania and Thaler, Franziska S and Brimberg, Lior and Schneider, Marc A and Muley, Thomas and Vural, Atay and Seifert-Held, Thomas and Endmayr, Verena and Höftberger, Romana and Faber, Jennifer and Klopstock, Thomas and Frahm, Silke and Gerdes, Lisa Ann and Meinl, Edgar and Mader, Simone},
title = {{Synaptophysin autoantibodies mediate synaptic dysfunction in cerebellar ataxia}},
journal = {Cell reports. Medicine},
year = {2026},
month = may,
volume = {7},
number = {6},
pages = {102822},
publisher = {Elsevier},
issn = {2666-3791},
doi = {10.1016/
url = {https://
pmid = {42155449},
pmcid = {PMC13293949}
}
RIS
TY - JOUR
AU - Ho, Samantha
AU - Wong, Hoi Kiu
AU - Shqau, Dorina
AU - Winklmeier, Stephan
AU - Grobe-Einsler, Marcus
AU - Rostasy, Kevin
AU - Kümpfel, Tania
AU - Thaler, Franziska S
AU - Brimberg, Lior
AU - Schneider, Marc A
AU - Muley, Thomas
AU - Vural, Atay
AU - Seifert-Held, Thomas
AU - Endmayr, Verena
AU - Höftberger, Romana
AU - Faber, Jennifer
AU - Klopstock, Thomas
AU - Frahm, Silke
AU - Gerdes, Lisa Ann
AU - Meinl, Edgar
AU - Mader, Simone
TI - Synaptophysin autoantibodies mediate synaptic dysfunction in cerebellar ataxia
T2 - Cell reports. Medicine
J2 - Cell Rep Med
PY - 2026
DA - 2026/
VL - 7
IS - 6
SP - 102822
SN - 2666-3791
PB - Elsevier
DO - 10.1016/
UR - https://
LA - en
ER -
CSL-JSON
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