Schwann cell nodal membrane disruption triggers bystander axonal degeneration in a Guillain-Barré syndrome mouse model
In Guillain-Barré syndrome (GBS), both axonal and demyelinating variants can be mediated by complement-fixing anti–GM1 ganglioside autoantibodies that target peripheral nerve axonal and Schwann cell (SC) membranes, respectively. Critically, the extent of axonal degeneration in both variants dictates...
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| Format: | Article |
| Language: | English |
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American Society for Clinical Investigation
2022-07-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI158524 |
| _version_ | 1797634630392741888 |
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| author | Rhona McGonigal Clare I. Campbell Jennifer A. Barrie Denggao Yao Madeleine E. Cunningham Colin L. Crawford Simon Rinaldi Edward G. Rowan Hugh J. Willison |
| author_facet | Rhona McGonigal Clare I. Campbell Jennifer A. Barrie Denggao Yao Madeleine E. Cunningham Colin L. Crawford Simon Rinaldi Edward G. Rowan Hugh J. Willison |
| author_sort | Rhona McGonigal |
| collection | DOAJ |
| description | In Guillain-Barré syndrome (GBS), both axonal and demyelinating variants can be mediated by complement-fixing anti–GM1 ganglioside autoantibodies that target peripheral nerve axonal and Schwann cell (SC) membranes, respectively. Critically, the extent of axonal degeneration in both variants dictates long-term outcome. The differing pathomechanisms underlying direct axonal injury and the secondary bystander axonal degeneration following SC injury are unresolved. To investigate this, we generated glycosyltransferase-disrupted transgenic mice that express GM1 ganglioside either exclusively in neurons [GalNAcT–/–-Tg(neuronal)] or glia [GalNAcT–/–-Tg(glial)], thereby allowing anti-GM1 antibodies to solely target GM1 in either axonal or SC membranes, respectively. Myelinated-axon integrity in distal motor nerves was studied in transgenic mice exposed to anti-GM1 antibody and complement in ex vivo and in vivo injury paradigms. Axonal targeting induced catastrophic acute axonal disruption, as expected. When mice with GM1 in SC membranes were targeted, acute disruption of perisynaptic glia and SC membranes at nodes of Ranvier (NoRs) occurred. Following glial injury, axonal disruption at NoRs also developed subacutely, progressing to secondary axonal degeneration. These models differentiate the distinctly different axonopathic pathways under axonal and glial membrane targeting conditions, and provide insights into primary and secondary axonal injury, currently a major unsolved area in GBS research. |
| first_indexed | 2024-03-11T12:10:19Z |
| format | Article |
| id | doaj.art-fb1eb71fa73646e493bb351632034731 |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:10:19Z |
| publishDate | 2022-07-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-fb1eb71fa73646e493bb3516320347312023-11-07T16:19:08ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382022-07-0113214Schwann cell nodal membrane disruption triggers bystander axonal degeneration in a Guillain-Barré syndrome mouse modelRhona McGonigalClare I. CampbellJennifer A. BarrieDenggao YaoMadeleine E. CunninghamColin L. CrawfordSimon RinaldiEdward G. RowanHugh J. WillisonIn Guillain-Barré syndrome (GBS), both axonal and demyelinating variants can be mediated by complement-fixing anti–GM1 ganglioside autoantibodies that target peripheral nerve axonal and Schwann cell (SC) membranes, respectively. Critically, the extent of axonal degeneration in both variants dictates long-term outcome. The differing pathomechanisms underlying direct axonal injury and the secondary bystander axonal degeneration following SC injury are unresolved. To investigate this, we generated glycosyltransferase-disrupted transgenic mice that express GM1 ganglioside either exclusively in neurons [GalNAcT–/–-Tg(neuronal)] or glia [GalNAcT–/–-Tg(glial)], thereby allowing anti-GM1 antibodies to solely target GM1 in either axonal or SC membranes, respectively. Myelinated-axon integrity in distal motor nerves was studied in transgenic mice exposed to anti-GM1 antibody and complement in ex vivo and in vivo injury paradigms. Axonal targeting induced catastrophic acute axonal disruption, as expected. When mice with GM1 in SC membranes were targeted, acute disruption of perisynaptic glia and SC membranes at nodes of Ranvier (NoRs) occurred. Following glial injury, axonal disruption at NoRs also developed subacutely, progressing to secondary axonal degeneration. These models differentiate the distinctly different axonopathic pathways under axonal and glial membrane targeting conditions, and provide insights into primary and secondary axonal injury, currently a major unsolved area in GBS research.https://doi.org/10.1172/JCI158524AutoimmunityNeuroscience |
| spellingShingle | Rhona McGonigal Clare I. Campbell Jennifer A. Barrie Denggao Yao Madeleine E. Cunningham Colin L. Crawford Simon Rinaldi Edward G. Rowan Hugh J. Willison Schwann cell nodal membrane disruption triggers bystander axonal degeneration in a Guillain-Barré syndrome mouse model The Journal of Clinical Investigation Autoimmunity Neuroscience |
| title | Schwann cell nodal membrane disruption triggers bystander axonal degeneration in a Guillain-Barré syndrome mouse model |
| title_full | Schwann cell nodal membrane disruption triggers bystander axonal degeneration in a Guillain-Barré syndrome mouse model |
| title_fullStr | Schwann cell nodal membrane disruption triggers bystander axonal degeneration in a Guillain-Barré syndrome mouse model |
| title_full_unstemmed | Schwann cell nodal membrane disruption triggers bystander axonal degeneration in a Guillain-Barré syndrome mouse model |
| title_short | Schwann cell nodal membrane disruption triggers bystander axonal degeneration in a Guillain-Barré syndrome mouse model |
| title_sort | schwann cell nodal membrane disruption triggers bystander axonal degeneration in a guillain barre syndrome mouse model |
| topic | Autoimmunity Neuroscience |
| url | https://doi.org/10.1172/JCI158524 |
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