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Multiple Sclerosis at the Crossroads of Autoimmunity and Neurodegeneration 2.0

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Dear Colleagues,

This Special Issue is the continuation of our previous Special Issue, “Multiple Sclerosis at the Crossroads of Autoimmunity and Neurodegeneration”.

There is increasing evidence that the slowly evolving disability in multiple sclerosis (MS) patients is, at least in part, disconnected from relapses. Recent findings indicate that, in addition to the well-recognized progressive forms of MS, a steady aggravation of neurological deficits may also occur in patients suffering from relapsing–remitting MS. Such a clinical progression is silent (i.e., independent from both clinical relapses and brain radiological activity) and was found to be closely associated with the rate of cervical spinal cord atrophy. While neurodegeneration in MS is usually thought to result from decades-long neuroinflammatory processes, these observations indicate that autoimmunity and neurodegeneration may actually develop concurrently. This Special Issue aims to provide an updated overview of our knowledge of the links between autoimmunity and neurodegeneration in MS. All papers relating to the general topic of this Special Issue will be considered. However, we specifically encourage the submission of articles addressing one or several of the following issues in the context of MS or related disorders:

Neuronal target antigens in MS and/or its animal model (experimental autoimmune encephalomyelitis);
Mechanisms favoring the intrathecal persistence of autoreactive lymphocytes;
Pro-degenerative vs. pro-regenerative impact of molecules involved in the resolution of CNS acute inflammation;
Insights into the mechanisms of inflammation-associated axonal loss and/or synaptic pruning.

Prof. Dr. Serge Nataf
Guest Editor

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Keywords

neurodegeneration
multiple sclerosis
autoimmunity
T lymphocytes
B lymphocytes
demyelination
axonal loss
synaptic pruning
microglia
astrocytes

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14 pages, 1006 KiB

Open AccessArticle

The Immunometabolic Gene N-Acetylglucosamine Kinase Is Uniquely Involved in the Heritability of Multiple Sclerosis Severity

by Serge Nataf, Marine Guillen and Laurent Pays

Int. J. Mol. Sci. 2024, 25(7), 3803; https://doi.org/10.3390/ijms25073803 - 28 Mar 2024

Viewed by 510

Abstract

The clinical severity of multiple sclerosis (MS), an autoimmune disorder of the central nervous system, is thought to be determined by environmental and genetic factors that have not yet been identified. In a recent genome-wide association study (GWAS), a single nucleotide polymorphism (SNP), rs10191329, has been associated with MS severity in two large independent cohorts of patients. Different approaches were followed by the authors to prioritize the genes that are transcriptionally regulated by such an SNP. It was concluded that the identified SNP regulates a group of proximal genes involved in brain resilience and cognitive abilities rather than immunity. Here, by conducting an alternative strategy for gene prioritization, we reached the opposite conclusion. According to our re-analysis, the main target of rs10191329 is N-Acetylglucosamine Kinase (NAGK), a metabolic gene recently shown to exert major immune functions via the regulation of the nucleotide-binding oligomerization domain-containing protein 2 (NOD2) pathway. To gain more insights into the immunometabolic functions of NAGK, we analyzed the currently known list of NAGK protein partners. We observed that NAGK integrates a dense network of human proteins that are involved in glucose metabolism and are highly expressed by classical monocytes. Our findings hold potentially major implications for the understanding of MS pathophysiology. Full article

(This article belongs to the Special Issue Multiple Sclerosis at the Crossroads of Autoimmunity and Neurodegeneration 2.0)

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9 pages, 505 KiB

Open AccessCommunication

No Association of Multiple Sclerosis with C9orf72 Hexanucleotide Repeat Size in an Austrian Cohort

by Theresa König, Fritz Leutmezer, Thomas Berger, Alexander Zimprich, Christiane Schmied, Elisabeth Stögmann and Tobias Zrzavy

Int. J. Mol. Sci. 2023, 24(14), 11254; https://doi.org/10.3390/ijms241411254 - 09 Jul 2023

Viewed by 860

Abstract

Multiple Sclerosis (MS) is a common immune-mediated disorder of the central nervous system that affects young adults and is characterized by demyelination and neurodegeneration. Recent studies have associated C9orf72 intermediate repeat expansions with MS. The objective of this study was to investigate whether C9orf72 repeat length is associated with MS or with a specific disease course in a monocentric Austrian MS cohort. Genotyping of 382 MS patients and 643 non-neurological controls for C9orf72 repeat expansions was performed. The study did not find a difference in the distribution of repeat numbers between controls and MS cases (median repeat units = 2; p = 0.39). Additionally, sub-analysis did not establish a link between intermediate repeats and MS (p = 0.23) and none of the patients with progressive disease course carried an intermediate allele (20–30 repeat units). Exploratory analysis for different cut-offs (of ≥7, ≥17, and ≥24) did not reveal any significant differences in allele frequencies between MS and controls. However, the study did identify a progressive MS patient with a pathogenic C9orf72 expansion and probable co-existing behavioral variant frontotemporal dementia (bvFTD) in a retrospective chart review. In conclusion, this study did not find evidence supporting an association between C9orf72 repeat length and MS or a specific disease course in the Austrian MS cohort. However, the identification of a progressive MS patient with a pathogenic C9orf72 expansion and probable co-existing with FTD highlights the complexity and challenges involved in recognizing distinct neurodegenerative diseases that may co-occur in MS patients. Full article

(This article belongs to the Special Issue Multiple Sclerosis at the Crossroads of Autoimmunity and Neurodegeneration 2.0)

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Multiple Sclerosis at the Crossroads of Autoimmunity and Neurodegeneration 2.0

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