Neuroinflammation in the normal-appearing white matter (NAWM) of the multiple sclerosis brain causes abnormalities at the nodes of Ranvier.

Patricia Gallego-Delgado,Nicholas D. Mazarakis,Joanna Meng,Eleanor Browne,A. Aldo Faisal,Mikael Simons,Rachel James,Richard Reynolds,Owain W. Howell,Swetha Umashankar,Carmen Picon,Li Tan

doi:10.1371/journal.pbio.3001008

Abstract

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.

Highlights

Multiple sclerosis (MS) is a neuroinflammatory disease of the central nervous system (CNS) characterised by focal and diffuse areas of inflammation, axonal degeneration and loss, demyelination, and gliosis [1]
In order to characterise paranodal junctions (PNJ) pathology present in human MS normal-appearing white matter (NAWM) tissue and its relationship to local microglial activation and axonal cytoskeleton disruption, NAWM regions of Neuroinflammation and node of Ranvier abnormalities in multiple sclerosis interest at least 4 to 5 mm away from a demyelinating lesion were carefully selected from snapfrozen tissue blocks incorporating the cerebral peduncle and the precentral gyrus, both of which have a high density of longitudinal axons
The nodes of Ranvier represent the only points of direct contact between myelin and the axon, at the paranodal axo-glial junctions [14,44], and it is suggested that these sites could be one of the targets of the immune mediated attacks in MS

Summary

Introduction

Multiple sclerosis (MS) is a neuroinflammatory disease of the central nervous system (CNS) characterised by focal and diffuse areas of inflammation, axonal degeneration and loss, demyelination, and gliosis [1]. The focus of MS research has for a long time been on the demyelinating lesions, neuronal damage and axonal loss are recognised as early and persistent factors in MS pathology [2,3] and may be the best predictors of long-term neurological decline [4]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

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