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...

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Main Authors: 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
Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
Format: Article
Language:English
Published: 2021
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Online Access:https://hdl.handle.net/10356/146129
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Institution: Nanyang Technological University
Language: English
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spelling sg-ntu-dr.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
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Science::Medicine
Multiple Sclerosis
Axon Stress
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
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.
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
format Article
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
author_sort Gallego-Delgado, Patricia
title 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_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_sort neuroinflammation in the normal-appearing white matter (nawm) of the multiple sclerosis brain causes abnormalities at the nodes of ranvier
publishDate 2021
url https://hdl.handle.net/10356/146129
_version_ 1759853753925632000