Patients with progressive subtype or greater disease severity in one study had strikingly lower levels of the sugar compound GlcNAc, a limiting substrate for a process that regulates immune activity and myelination.
N-glycan branching modulates the availability of cell surface receptors and, as pre-described from mouse models, a deficit promotes inflammatory demyelination, reduced myelination and neurodegeneration. The simple sugar N-acetylglucosamine (GlcNAc) is a rate-limiting substrate for N-glycan branching. Previous studies suggested that N-glycosylation may play a role in multiple sclerosis and that the two may be linked due to environmental factors or genetic sequence variants. For example, work in humans has shown that severe hypomyelination of the central nervous system may be the result of loss-of-function variants in PGM3, a gene necessary for the formation of branched N-glycans from GlcNAc.1
In the first studies of its kind, researchers have now investigated something that was previously little known: endogenous serum GlcNAc levels in patients with MS.2
They conducted two cross-sectional studies at two academic MS centres in the USA and Germany: a first study with 54 MS patients and 66 healthy controls, and a confirmatory study with 180 MS patients. They determined serum concentrations of GlcNAc and its stereoisomer, N-acetylhexosamine (HexNAc), using an advanced form of mass spectroscopy.
In patients with relapsing-remitting MS, serum GlcNAc levels were only minimally lower than in healthy individuals, while in patients with progressive MS they were significantly reduced. Lower HexNAc levels also correlated significantly with poorer EDSS (expanded disability status scale), smaller thalamic volume, and thinner retinal nerve fibre layer. In addition, patients with lower baseline HexNAc levels experienced significantly greater brain volume loss after 18 months.
Previous work suggests that N-glycan branching or GlcNAc can reduce proinflammatory responses, promote myelin repair and reduce neurodegeneration. A role for this is that modification of cell surface receptors with branched N-glycans coordinates cell growth and differentiation by controlling glycoprotein clustering, signal transduction and endocytosis.
In a study3 published a few months ago, authors from the same team reported that GlcNAc and N-glycan branching trigger oligodendrogenesis from progenitor cells in mice. Oral administration of GlcNAc to lactating mice promoted primary myelination in neonates, while genetic blocking of N-glycan branching significantly inhibited it. In adult mice with toxin-induced demyelination, oral GlcNAc prevented neuroaxonal damage by driving myelin repair. Already in this work, they found that in MS patients, serum GlcNAc levels inversely correlated with demyelination and microstructural damage on imaging.
"Our data identify N-glycan branching and GlcNAc as critical regulators of primary myelination and myelin repair and suggest that oral GlcNAc may be neuroprotective in demyelinating diseases such as MS," the authors concluded.3
Taken together, the data from both papers suggest that deficiency of GlcNAc (and its isomers) may be linked to disease progression and neurodegeneration. Further studies are needed to clarify, for example, the influence of factors such as diet or physical activity. The authors hope that "the identification of simple molecular biomarkers for progressive multiple sclerosis (PMS) is an unmet clinical need and could allow early diagnosis, monitoring of treatment success and the development of new treatment approaches".
References:
1. Study Identifies Potential Molecular Biomarker of Progressive MS. AJMC https://www.ajmc.com/view/study-identifies-potential-molecular-biomarker-of-progressive-ms.
2. Brandt, A. U. et al. Association of a Marker of N-Acetylglucosamine With Progressive Multiple Sclerosis and Neurodegeneration. JAMA Neurol (2021) doi:10.1001/jamaneurol.2021.1116.
3. Sy, M. et al. N-acetylglucosamine drives myelination by triggering oligodendrocyte precursor cell differentiation. J Biol Chem 295, 17413–17424 (2020).