Human autoantibodies to amphiphysin induce defective presynaptic vesicle dynamics and composition
Abstract
See Irani (doi:10.1093/awv364) for a scientific commentary on this article. Stiff-person syndrome is the prototype of a central nervous system disorder with autoantibodies targeting presynaptic antigens. Patients with paraneoplastic stiff-person syndrome may harbour autoantibodies to the BAR (Bin/Amphiphysin/Rvs) domain protein amphiphysin, which target its SH3 domain. These patients have neurophysiological signs of compromised central inhibition and respond to symptomatic treatment with medication enhancing GABAergic transmission. High frequency neurotransmission as observed in tonic GABAergic interneurons relies on fast exocytosis of neurotransmitters based on compensatory endocytosis. As amphiphysin is involved in clathrin-mediated endocytosis, patient autoantibodies are supposed to interfere with this function, leading to disinhibition by reduction of GABAergic neurotransmission. We here investigated the effects of human anti-amphiphysin autoantibodies on structural components of presynaptic boutons ex vivo and in vitro using electron microscopy and super-resolution direct stochastic optical reconstruction microscopy. Ultrastructural analysis of spinal cord presynaptic boutons was performed after in vivo intrathecal passive transfer of affinity-purified human anti-amphiphysin autoantibodies in rats and revealed signs of markedly disabled clathrin-mediated endocytosis. This was unmasked at high synaptic activity and characterized by a reduction of the presynaptic vesicle pool, clathrin coated intermediates, and endosome-like structures. Super-resolution microscopy of inhibitory GABAergic presynaptic boutons in primary neurons revealed that specific human anti-amphiphysin immunoglobulin G induced an increase of the essential vesicular protein synaptobrevin 2 and a reduction of synaptobrevin 7. This constellation suggests depletion of resting pool vesicles and trapping of releasable pool vesicular proteins at the plasma membrane. Similar effects were found in amphiphysin-deficient neurons from knockout mice. Application of specific patient antibodies did not show additional effects. Blocking alternative pathways of clathrin-independent endocytosis with brefeldin A reversed the autoantibody induced effects on molecular vesicle composition. Endophilin as an interaction partner of amphiphysin showed reduced clustering within presynaptic terminals. Collectively, these results point towards an autoantibody-induced structural disorganization in GABAergic synapses with profound changes in presynaptic vesicle pools, activation of alternative endocytic pathways, and potentially compensatory rearrangement of proteins involved in clathrin-mediated endocytosis. Our findings provide novel insights into synaptic pathomechanisms in a prototypic antibody-mediated central nervous system disease, which may serve as a proof-of-principle example in this evolving group of autoimmune disorders associated with autoantibodies to synaptic antigens.
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Human autoantibodies to AMPH induce defective presynaptic vesicle dynamics and composition, leading to decreased GABAergic transmission.
“human autoantibodies to AMPH, which are observed in rare diseases (e.g., Stiff person syndrome), have been shown to induce defective presynaptic vesicle dynamics and composition, leading to decreased GABAergic transmission (37).”
From Molecular subtyping of Alzheimer’s disease using RNA sequencing data reveals novel mechanisms and targets (2021) · cites this paper as [37]
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Synaptopathies: synaptic dysfunction in neurological disorders – A review from students to students
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“, Stiff person syndrome), have been shown to induce defective presynaptic vesicle dynamics and composition, leading to decreased GABAergic transmission (37).”
Background
- Authors
- Werner, C., Pauli, M., Doose, S., Weishaupt, A., Haselmann, H., Grünewald, B., Sauer, M., Heckmann, M., Toyka, K. V., Asan, E., Sommer, C., & Geis, C.
- Affiliations
- University of Würzburg (DE)
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-11-18
- Volume
- 139
- Issue
- 2
- Pages
- 365-379
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- OpenAlex
- W2174733793
- Cited by
- 75
- References
- 57
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 6 · 2023: 11 · 2022: 7 · 2021: 5 · 2020: 7 · 2019: 11 · 2018: 9 · 2017: 5 · 2016: 7
- FWCI
- 4.94
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Topics
- Health Sciences › Medicine › Neurology › Autoimmune Neurological Disorders and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- amphiphysin, stiff person syndrome, presynaptic vesicles, clathrin-mediated endocytosis, GABAergic synapses, synaptobrevin 2, endophilin, synaptic ultrastructure
- MeSH terms
- Animals, Autoantibodies, Cells, Cultured, Female, Humans, Injections, Spinal, Mice, Inbred C57BL, Nerve Tissue Proteins, Neurons, Pregnancy, Rats, Inbred Lew, Synaptic Vesicles, Stiff-Person Syndrome, Presynaptic Terminals, Mice, Rats
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