A new University of California, Irvine-led study finds low serum levels of the sugar N-acetylglucosamine (GlcNAc), is associated with progressive disability and neurodegeneration in multiple sclerosis (MS).
The study, done in collaboration with researchers from Charité – Universitätsmedizin Berlin, Germany, and the University of Toronto, Canada, is titled, “Association of a Marker of N-Acetylglucosamine With Progressive Multiple Sclerosis and Neurodegeneration,” The study was published this week in JAMA Neurology.
The study suggests that GlcNAc, which has been previously shown to promote re-myelination and suppress neurodegeneration in animal models of MS, is reduced in serum of progressive MS patients and those with worse clinical disability and neurodegeneration.
“We found the serum levels of a marker of GlcNAc was markedly reduced in progressive MS patients compared to healthy controls and patients with relapsing-remitting multiple sclerosis” explained Michael Demetriou, MD, PhD, FRCP(C), professor of neurology, microbiology and molecular genetics at UCI School of Medicine, and senior author on the paper.
First author of the study, Alexander Brandt, MD, adjunct associate professor of neurology at the UCI School of Medicine and previously associated with the Experimental and Clinical Research Center, Charité – Universitätsmedizin Berlin and Max Delbrueck Center for Molecular Medicine, Germany, added, “Lower GlcNAc serum marker levels correlated with multiple measures of neurodegeneration in MS, namely worse expanded disability status scale scores, lower thalamic volume, and thinner retinal nerve fiber layer. Also, low baseline serum levels correlated with a greater percentage of brain volume loss at 18 months,” he said.
GlcNAc regulates protein glycosylation, a fundamental process that decorates the surface of all cells with complex sugars. Previous preclinical, human genetic and ex vivo human mechanistic studies revealed that GlcNAc reduces proinflammatory immune responses, promotes myelin repair, and decreases neurodegeneration.
Combined with the new findings, the data suggest that GlcNAc deficiency may promote progressive disease and neurodegeneration in patients with MS. However, additional human clinical studies are required to confirm this hypothesis.
“Our findings open new potential avenues to identify patients at risk of disease progression and neurodegeneration, so clinicians can develop and adjust therapies accordingly,” said Michael Sy, MD, PhD, assistant professor in residence in the Department of Neurology at UCI and a co-author of the study.
MS is characterized by recurrent episodes of neurologic dysfunction resulting from acute inflammatory demyelination. Progressive MS is distinguished by continuous inflammation, failure to remyelinate, and progressive neurodegeneration, causing accrual of irreversible neurologic disability.
Neurodegeneration is the major contributor to progressive neurological disability in MS patients, yet mechanisms are poorly understood and there are no current treatments for neurodegeneration.
Myelination plays an important role in cognitive development and in demyelinating diseases like multiple sclerosis (MS), where failure of remyelination promotes permanent neuro-axonal damage. Modification of cell surface receptors with branched N-glycans coordinates cell growth and differentiation by controlling glycoprotein clustering, signaling, and endocytosis.
GlcNAc is a rate-limiting metabolite for N-glycan branching. Here we report that GlcNAc and N-glycan branching trigger oligodendrogenesis from precursor cells by inhibiting platelet-derived growth factor receptor-α cell endocytosis. Supplying oral GlcNAc to lactating mice drives primary myelination in newborn pups via secretion in breast milk, whereas genetically blocking N-glycan branching markedly inhibits primary myelination.
In adult mice with toxin (cuprizone)-induced demyelination, oral GlcNAc prevents neuro-axonal damage by driving myelin repair. In MS patients, endogenous serum GlcNAc levels inversely correlated with imaging measures of demyelination and microstructural damage. 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 like MS.
Myelination of axons by oligodendrocytes in the central nervous system plays a critical role in normal cognitive development and function and in demyelinating disease such as multiple sclerosis (MS) (1, 2). In addition to speeding conduction of the action potential, myelination supports axon health and survival (3, 4, 5).
In MS, remyelination of demyelinated axons by oligodendrocytes is often incomplete despite the presence of abundant oligodendrocyte precursor cells (OPC) throughout the brain (6, 7, 8, 9, 10). The molecular mechanisms that block remyelination in MS are incompletely understood, and there is a lack of therapies to promote myelin repair.
Failure to adequately remyelinate is influenced by the microenvironment of the MS lesion, where reactive astrocytes, microglia, and macrophages produce various inhibitory factors leading to disruption in OPC differentiation, oligodendrocyte migration, process outgrowth, and attachment to axons (11).
Multiple studies have identified molecules that limit OPC differentiation into myelin-producing cells including LINGO-1 (12), various extracellular matrix proteins (13, 14), and myelin debris (15). Thus, increasing OPC differentiation has become an important strategy for promoting remyelination in MS and other demyelinating diseases (16).
Cell surface and secreted proteins are co- and post-translationally modified on Asn(N) by the addition of carbohydrates (N-glycans) in the endoplasmic reticulum and subsequently remodeled in the Golgi. The degree of GlcNAc branching in N-glycans promotes binding to galectins, a family of sugar-binding proteins (Fig. S1A).
Polyvalent galectin-glycoprotein interactions at the cell surface form a macromolecular lattice that simultaneously controls the movement, clustering, and/or endocytosis of multiple receptors and transporters to control signaling, cell growth, differentiation, and death (17, 18, 19, 20, 21, 22, 23, 24).
For example, N-glycan branching controls epithelial cell growth by regulating receptor tyrosine kinases endocytosis (17, 18, 19, 20), promotes glucose uptake in mesenchymal and pancreatic β cells by inhibiting glucose transporter endocytosis (19, 25), and reduces T-cell, B-cell, and neutrophil pro-inflammatory responses by coregulating the clustering and/or endocytosis of multiple glycoproteins (17, 21, 23, 27, 28, 29).
These mechanisms in turn impact cancer, type II diabetes, and autoimmunity (20). For example, reductions in N-glycan branching are associated with MS and promote both inflammatory demyelination and neurodegeneration in mice, the latter by an unknown mechanism (17, 30, 31, 32, 33, 34, 35, 36).
Given the diverse and pleiotropic effects of N-glycan branching, identifying and manipulating regulatory mechanisms may provide new insights into disease pathogenesis and opportunities for therapeutic intervention. In this regard, metabolism is a critical regulator of N-glycan branching by controlling availability of the sugar-nucleotide UDP-GlcNAc, the substrate used by the Mgat family of N-glycan branching enzymes (19, 20, 24, 37, 38).
UDP-GlcNAc is generated in the hexosamine pathway de novo from glucose or by salvage from GlcNAc. Extracellular GlcNAc enters cells through micropinocytosis, with supplementation of cells or mice with GlcNAc inhibiting pro-inflammatory T-cell responses and murine models of inflammatory demyelination by enhancing N-glycan branching (19, 31, 37, 38).
Targeted deletion of galectin-3, a ligand for N-glycan branching, leads to decreased production of oligodendrocytes, poor myelination of axons, and reduced ability to remyelinate after injury (39). In humans, loss-of-function mutations in PGM3, a gene required to generate branched N-glycans from GlcNAc, display reduced branching and severe CNS hypomyelination (40). Platelet-derived growth factor–AA plays a critical role in oligodendrogenesis (41), with its receptor (PDGFRα) expressed in oligodendrocyte progenitor/precursor cells (42).
In epithelial cells, N-glycan branching deficiency reduces PDGFRα surface expression by enhancing loss via endocytosis, leading to reduced signaling (18). Thus, here we examine the hypothesis that GlcNAc may provide an oral therapeutic to raise N-glycan branching in OPCs, promote myelination, and reduce the potential for neurodegeneration by initiating oligodendrocyte differentiation via enhanced PDGFRα surface expression and signaling in OPCs.
reference link: https://www.jbc.org/article/S0021-9258(17)50630-4/fulltext
Original Research: Open access.
“Association of a Marker of N-Acetylglucosamine With Progressive Multiple Sclerosis and Neurodegeneration” by Michael Demetriou et al. JAMA Neurology