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Complement-membrane regulatory proteins are absent from the nodes of Ranvier in the peripheral nervous system
BACKGROUND: Homozygous CD59-deficient patients manifest with recurrent peripheral neuropathy resembling Guillain-Barré syndrome (GBS), hemolytic anemia and recurrent strokes. Variable mutations in CD59 leading to loss of function have been described and, overall, 17/18 of patients with any mutation...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10594684/ https://www.ncbi.nlm.nih.gov/pubmed/37875972 http://dx.doi.org/10.1186/s12974-023-02920-9 |
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author | Karbian, Netanel Eshed-Eisenbach, Yael Zeibak, Marian Tabib, Adi Sukhanov, Natasha Vainshtein, Anya Morgan, B. Paul Fellig, Yakov Peles, Elior Mevorach, Dror |
author_facet | Karbian, Netanel Eshed-Eisenbach, Yael Zeibak, Marian Tabib, Adi Sukhanov, Natasha Vainshtein, Anya Morgan, B. Paul Fellig, Yakov Peles, Elior Mevorach, Dror |
author_sort | Karbian, Netanel |
collection | PubMed |
description | BACKGROUND: Homozygous CD59-deficient patients manifest with recurrent peripheral neuropathy resembling Guillain-Barré syndrome (GBS), hemolytic anemia and recurrent strokes. Variable mutations in CD59 leading to loss of function have been described and, overall, 17/18 of patients with any mutation presented with recurrent GBS. Here we determine the localization and possible role of membrane-bound complement regulators, including CD59, in the peripheral nervous systems (PNS) of mice and humans. METHODS: We examined the localization of membrane-bound complement regulators in the peripheral nerves of healthy humans and a CD59-deficient patient, as well as in wild-type (WT) and CD59a-deficient mice. Cross sections of teased sciatic nerves and myelinating dorsal root ganglia (DRG) neuron/Schwann cell cultures were examined by confocal and electron microscopy. RESULTS: We demonstrate that CD59a-deficient mice display normal peripheral nerve morphology but develop myelin abnormalities in older age. They normally express myelin protein zero (P0), ankyrin G (AnkG), Caspr, dystroglycan, and neurofascin. Immunolabeling of WT nerves using antibodies to CD59 and myelin basic protein (MBP), P0, and AnkG revealed that CD59 was localized along the internode but was absent from the nodes of Ranvier. CD59 was also detected in blood vessels within the nerve. Finally, we show that the nodes of Ranvier lack other complement-membrane regulatory proteins, including CD46, CD55, CD35, and CR1-related gene-y (Crry), rendering this area highly exposed to complement attack. CONCLUSION: The Nodes of Ranvier lack CD59 and are hence not protected from complement terminal attack. The myelin unit in human PNS is protected by CD59 and CD55, but not by CD46 or CD35. This renders the nodes and myelin in the PNS vulnerable to complement attack and demyelination in autoinflammatory Guillain-Barré syndrome, as seen in CD59 deficiency. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-023-02920-9. |
format | Online Article Text |
id | pubmed-10594684 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-105946842023-10-25 Complement-membrane regulatory proteins are absent from the nodes of Ranvier in the peripheral nervous system Karbian, Netanel Eshed-Eisenbach, Yael Zeibak, Marian Tabib, Adi Sukhanov, Natasha Vainshtein, Anya Morgan, B. Paul Fellig, Yakov Peles, Elior Mevorach, Dror J Neuroinflammation Research BACKGROUND: Homozygous CD59-deficient patients manifest with recurrent peripheral neuropathy resembling Guillain-Barré syndrome (GBS), hemolytic anemia and recurrent strokes. Variable mutations in CD59 leading to loss of function have been described and, overall, 17/18 of patients with any mutation presented with recurrent GBS. Here we determine the localization and possible role of membrane-bound complement regulators, including CD59, in the peripheral nervous systems (PNS) of mice and humans. METHODS: We examined the localization of membrane-bound complement regulators in the peripheral nerves of healthy humans and a CD59-deficient patient, as well as in wild-type (WT) and CD59a-deficient mice. Cross sections of teased sciatic nerves and myelinating dorsal root ganglia (DRG) neuron/Schwann cell cultures were examined by confocal and electron microscopy. RESULTS: We demonstrate that CD59a-deficient mice display normal peripheral nerve morphology but develop myelin abnormalities in older age. They normally express myelin protein zero (P0), ankyrin G (AnkG), Caspr, dystroglycan, and neurofascin. Immunolabeling of WT nerves using antibodies to CD59 and myelin basic protein (MBP), P0, and AnkG revealed that CD59 was localized along the internode but was absent from the nodes of Ranvier. CD59 was also detected in blood vessels within the nerve. Finally, we show that the nodes of Ranvier lack other complement-membrane regulatory proteins, including CD46, CD55, CD35, and CR1-related gene-y (Crry), rendering this area highly exposed to complement attack. CONCLUSION: The Nodes of Ranvier lack CD59 and are hence not protected from complement terminal attack. The myelin unit in human PNS is protected by CD59 and CD55, but not by CD46 or CD35. This renders the nodes and myelin in the PNS vulnerable to complement attack and demyelination in autoinflammatory Guillain-Barré syndrome, as seen in CD59 deficiency. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-023-02920-9. BioMed Central 2023-10-24 /pmc/articles/PMC10594684/ /pubmed/37875972 http://dx.doi.org/10.1186/s12974-023-02920-9 Text en © The Author(s) 2023 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/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Karbian, Netanel Eshed-Eisenbach, Yael Zeibak, Marian Tabib, Adi Sukhanov, Natasha Vainshtein, Anya Morgan, B. Paul Fellig, Yakov Peles, Elior Mevorach, Dror Complement-membrane regulatory proteins are absent from the nodes of Ranvier in the peripheral nervous system |
title | Complement-membrane regulatory proteins are absent from the nodes of Ranvier in the peripheral nervous system |
title_full | Complement-membrane regulatory proteins are absent from the nodes of Ranvier in the peripheral nervous system |
title_fullStr | Complement-membrane regulatory proteins are absent from the nodes of Ranvier in the peripheral nervous system |
title_full_unstemmed | Complement-membrane regulatory proteins are absent from the nodes of Ranvier in the peripheral nervous system |
title_short | Complement-membrane regulatory proteins are absent from the nodes of Ranvier in the peripheral nervous system |
title_sort | complement-membrane regulatory proteins are absent from the nodes of ranvier in the peripheral nervous system |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10594684/ https://www.ncbi.nlm.nih.gov/pubmed/37875972 http://dx.doi.org/10.1186/s12974-023-02920-9 |
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