Neuroinflammation in the normal-appearing white matter (NAWM) of the multiple sclerosis brain causes abnormalities at the nodes of Ranvier
Changes to the structure of nodes of Ranvier in the normal-appearing white matter (NAWM) of multiple sclerosis (MS) brains are associated with chronic inflammation. We show that the paranodal domains in MS NAWM are longer on average than control, with Kv1.2 channels dislocated into the paranode. The...
| Main Authors: | , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
| Published: |
2021
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| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/146129 |
| _version_ | 1811679743592890368 |
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| author | Gallego-Delgado, Patricia James, Rachel Browne, Eleanor Meng, Joanna Umashankar, Swetha Tan, Li Picon, Carmen Mazarakis, Nicholas D. Faisal, A. Aldo Howell, Owain W. Reynolds, Richard |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Gallego-Delgado, Patricia James, Rachel Browne, Eleanor Meng, Joanna Umashankar, Swetha Tan, Li Picon, Carmen Mazarakis, Nicholas D. Faisal, A. Aldo Howell, Owain W. Reynolds, Richard |
| author_sort | Gallego-Delgado, Patricia |
| collection | NTU |
| description | Changes to the structure of nodes of Ranvier in the normal-appearing white matter (NAWM) of multiple sclerosis (MS) brains are associated with chronic inflammation. We show that the paranodal domains in MS NAWM are longer on average than control, with Kv1.2 channels dislocated into the paranode. These pathological features are reproduced in a model of chronic meningeal inflammation generated by the injection of lentiviral vectors for the lymphotoxin-α (LTα) and interferon-γ (IFNγ) genes. We show that tumour necrosis factor (TNF), IFNγ, and glutamate can provoke paranodal elongation in cerebellar slice cultures, which could be reversed by an N-methyl-D-aspartate (NMDA) receptor blocker. When these changes were inserted into a computational model to simulate axonal conduction, a rapid decrease in velocity was observed, reaching conduction failure in small diameter axons. We suggest that glial cells activated by pro-inflammatory cytokines can produce high levels of glutamate, which triggers paranodal pathology, contributing to axonal damage and conduction deficits. |
| first_indexed | 2024-10-01T03:14:00Z |
| format | Journal Article |
| id | ntu-10356/146129 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T03:14:00Z |
| publishDate | 2021 |
| record_format | dspace |
| spelling | ntu-10356/1461292023-03-05T16:48:33Z Neuroinflammation in the normal-appearing white matter (NAWM) of the multiple sclerosis brain causes abnormalities at the nodes of Ranvier Gallego-Delgado, Patricia James, Rachel Browne, Eleanor Meng, Joanna Umashankar, Swetha Tan, Li Picon, Carmen Mazarakis, Nicholas D. Faisal, A. Aldo Howell, Owain W. Reynolds, Richard Lee Kong Chian School of Medicine (LKCMedicine) Science::Medicine Multiple Sclerosis Axon Stress Changes to the structure of nodes of Ranvier in the normal-appearing white matter (NAWM) of multiple sclerosis (MS) brains are associated with chronic inflammation. We show that the paranodal domains in MS NAWM are longer on average than control, with Kv1.2 channels dislocated into the paranode. These pathological features are reproduced in a model of chronic meningeal inflammation generated by the injection of lentiviral vectors for the lymphotoxin-α (LTα) and interferon-γ (IFNγ) genes. We show that tumour necrosis factor (TNF), IFNγ, and glutamate can provoke paranodal elongation in cerebellar slice cultures, which could be reversed by an N-methyl-D-aspartate (NMDA) receptor blocker. When these changes were inserted into a computational model to simulate axonal conduction, a rapid decrease in velocity was observed, reaching conduction failure in small diameter axons. We suggest that glial cells activated by pro-inflammatory cytokines can produce high levels of glutamate, which triggers paranodal pathology, contributing to axonal damage and conduction deficits. Published version 2021-01-27T04:31:07Z 2021-01-27T04:31:07Z 2020 Journal Article Gallego-Delgado, P., James, R., Browne, E., Meng, J., Umashankar, S., Tan, L., . . . Reynolds, R. (2020). Neuroinflammation in the normal-appearing white matter (NAWM) of the multiple sclerosis brain causes abnormalities at the nodes of Ranvier. PLOS Biology, 18(12), e3001008-. doi:10.1371/journal.pbio.3001008 1544-9173 https://hdl.handle.net/10356/146129 10.1371/journal.pbio.3001008 33315860 2-s2.0-85097677754 12 18 en PLoS biology © 2020 Gallego-Delgado et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. application/pdf |
| spellingShingle | Science::Medicine Multiple Sclerosis Axon Stress Gallego-Delgado, Patricia James, Rachel Browne, Eleanor Meng, Joanna Umashankar, Swetha Tan, Li Picon, Carmen Mazarakis, Nicholas D. Faisal, A. Aldo Howell, Owain W. Reynolds, Richard Neuroinflammation in the normal-appearing white matter (NAWM) of the multiple sclerosis brain causes abnormalities at the nodes of Ranvier |
| title | Neuroinflammation in the normal-appearing white matter (NAWM) of the multiple sclerosis brain causes abnormalities at the nodes of Ranvier |
| title_full | Neuroinflammation in the normal-appearing white matter (NAWM) of the multiple sclerosis brain causes abnormalities at the nodes of Ranvier |
| title_fullStr | Neuroinflammation in the normal-appearing white matter (NAWM) of the multiple sclerosis brain causes abnormalities at the nodes of Ranvier |
| title_full_unstemmed | Neuroinflammation in the normal-appearing white matter (NAWM) of the multiple sclerosis brain causes abnormalities at the nodes of Ranvier |
| title_short | Neuroinflammation in the normal-appearing white matter (NAWM) of the multiple sclerosis brain causes abnormalities at the nodes of Ranvier |
| title_sort | neuroinflammation in the normal appearing white matter nawm of the multiple sclerosis brain causes abnormalities at the nodes of ranvier |
| topic | Science::Medicine Multiple Sclerosis Axon Stress |
| url | https://hdl.handle.net/10356/146129 |
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