Multiple sclerosis (MS) is characterized by recurrent episodes of neurologic dysfunction resulting from acute inflammatory demyelination.1 Progressive MS is distinguished by continuous inflammation, failure to remyelinate, and progressive neurodegeneration, causing accrual of irreversible neurologic disability. After approximately 20 years, relapsing-remitting MS (RRMS) converts to secondary-progressive MSfor many patients, while approximately 10% of patients have a primary progressive disease course from onset. However, disease progression outside relapses is not limited to the progressive forms of the disease; instead, it is an inherent feature from the early stages and throughout all disease courses.
Today’s therapeutic approaches are based on the assumption that the immune system is making a mistake and waging an inappropriate attack on the layer of myelin that surrounds and insulates the nerve cells’ long, cable-like branches called axons. In progressive MS, neurodegenerative processes steadily multiply and cause more and more neurons in the brain and spinal cord to die. However, we still do not know what exactly causes this disease variant.”
Dr. Alexander Brandt, lead author together with Professor Friedemann Paul from the Experimental and Clinical Research Center, a joint institution of Charité Universitätsmedizin Berlin and the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), as well as eleven colleagues from Berlin, Irvine and Toronto, the authors hoep they can shed some more light on the subject. As the team reports in their study, it appears that the simple sugar N-acetylglucosamine, or GlcNAc for short, could play an important role in the development of progressive MS. Inside an organism, GlcNAc and other sugar molecules attach to proteins on the cell surface in the form of chains. This mechanism, which is known as glycosylation, controls various cell functions by forming branched structures from these sugar chains. The original article is now published in the journal JAMA Neurology.
The authors studied 120 subjects from Irvine and were able to show that, in this particularly severe form of the disease, there are significantly lower concentrations of N-acetylglucosamine in the blood serum than there are in healthy people or patients with relapsing-remitting MS. In another study of 180 patients from Berlin with relapsing-remitting or progressive MS, we also found that low serum levels of GlcNAc are associated with the development of the progressive form of the disease, clinical disability and neurodegeneration. This opens up potential new avenues for identifying, at an early stage, which patients are at higher risk of progressive MS and adjusting their treatment accordingly.
Previously, Brandt, Demetriou and other researchers working with the then lead author Dr. Michael Sy from UC Irvine conducted a study which is published in the Journal of Biological Chemistry. They had administered GlcNAc to lactating mice and found that the animals passed on this simple sugar, which incidentally is also contained in human breast milk, to their offspring. This stimulated primary myelination of the neuronal axons in the young animals. They also observed in the mouse experiments that N-acetylglucosamine activates myelin progenitor cells, thus promoting both primary myelination and the repair of damaged myelin.
The researchers therefore hope that GlcNAc not only has potential as a suitable biomarker for progressive MS, but could also pave the way for new therapeutic strategies. They hope is that we can use GlcNAc and the associated glycosylation mechanism to promote myelin repair and thus reduce neurodegeneration. An initial, as-yet-unpublished phase I trial has just been completed with around 30 subjects, where the scientists investigated the safety of taking GlcNAc in certain doses. If it is shown to be safe, the scientists hope to be able to conduct further studies into this simple sugar’s possible efficacy as an MS therapy.
The authors reported that GlcNAc plus its stereoisomers are markedly reduced in PMS in 2 independent cohorts and that serum HexNAc levels are correlated with clinical disability and neuroimaging markers of neurodegeneration. Understanding immune mechanisms in RRMS has led to the development of multiple drugs that are successfully used clinically
Molecular biomarker studies in MS have led to several high-profile failures, in which the initial findings could not be independently verified, often with biomarkers of unclear mechanistic relevance to MS. In contrast, GlcNAc and N-glycan branching have been intensely studied as already summarized, and multiple cellular pathways important to progression and neurodegeneration in MS have been identified with different levels of evidence. Moreover, we used multiple methods to minimize potential bias as a source of error in our investigations. The LC-MS/MS analysis of serum HexNAc was performed in a blinded fashion by an independent investigator who was not involved in the study design and objective. We confirmed our main finding in a second cohort, which was managed in a different MS center in a different country by a different team of clinician-scientists. Third, all of the investigators of diagnostic, clinical disability, and neuroimaging measures in the confirmatory cohort were blinded to serum HexNAc levels.
The study identifies for the first time that reduced serum HexNAc levels as a potential molecular biomarker of PMS. These new clinical data build on preclinical, human ex vivo, and genetic research establishing a role of N-glycan branching and its metabolite GlcNAc in MS-relevant disease processes, including inflammation but, importantly, also myelination and neurodegeneration. It also suggests that a fundamental molecular process, N-glycan branching, may be altered in PMS, separating it from RRMS. Further studies are required to develop our understanding of the relevance of N-glycan branching and GlcNAc in PMS and of the clinical research and/or clinical management of disease progression in MS.
Alexander U. Brandt, Michael Sy, Judith Bellmann-Strobl, Barbara L. Newton, Judy Pawling, Hanna G. Zimmermann, Zhaoxia Yu, Claudia Chien, Jan Dörr, Jens Th. Wuerfel, James W. Dennis, Friedemann Paul, Michael Demetriou. Association of a Marker of N-Acetylglucosamine With Progressive Multiple Sclerosis and Neurodegeneration. JAMA Neurology, 2021; DOI: 10.1001/jamaneurol.2021.1116Go To JAMA Neurology