bims-meglyc 2025-03-02 papers

bims-meglyc

Biomed News

on Metabolic disorders affecting glycosylation

Issue of 2025–03–02
five papers selected by
Silvia Radenkovic, UMC Utrecht

Niemann-Pick C-like Endolysosomal Dysfunction in DHDDS Patient Cells, a Congenital Disorder of Glycosylation, Can Be Treated with Miglustat.
"Trafficking Disorders: Phenotypical Similarities and Differences With Other IMDs".
Malformations of Core M3 on α-Dystroglycan Are the Leading Cause of Dystroglycanopathies.
Quantification of Glycosaminoglycans in Urine by Isotope Dilution Liquid Chromatography-Electrospray Ionization Tandem Mass Spectrometry.
Epalrestat Alleviates Reactive Oxygen Species and Endoplasmic Reticulum Stress by Maintaining Glycosylation in IMS32 Schwann Cells Under Exposure to Galactosemic Conditions.

Int J Mol Sci. 2025 Feb 10. pii: 1471. [Epub ahead of print]26(4):

Niemann-Pick C-like Endolysosomal Dysfunction in DHDDS Patient Cells, a Congenital Disorder of Glycosylation, Can Be Treated with Miglustat.

Hannah L Best, Sophie R Cook, Helen Waller-Evans, Emyr Lloyd-Evans.

  DHDDS (dehydrodolichol diphosphate synthetase) and NgBR (Nogo-B Receptor) collectively form an enzymatic complex important for the synthesis of dolichol, a key component of protein N-glycosylation. Mutations in DHDDS and the gene encoding NgBR (NUS1) are associated with neurodevelopmental disorders that clinically present with epilepsy, motor impairments, and developmental delay. Previous work has demonstrated both DHDDS and NgBR can also interact with NPC2 (Niemann-Pick C (NPC) type 2), a protein which functions to traffic cholesterol out of the lysosome and, when mutated, can cause a lysosomal storage disorder (NPC disease) characterised by an accumulation of cholesterol and glycosphingolipids. Abnormal cholesterol accumulation has also been reported in cells from both individuals and animal models with mutations in NUS1, and suspected lipid storage has been shown in biopsies from individuals with mutations in DHDDS. Our findings provide further evidence for overlap between NPC2 and DHDDS disorders, showing that DHDDS patient fibroblasts have increased lysosomal volume, store cholesterol and ganglioside GM1, and have altered lysosomal Ca2+ homeostasis. Treatment of DHDDS cells, with the approved NPC small molecule therapy, miglustat, improves these disease-associated phenotypes, identifying a possible therapeutic option for DHDDS patients. These data suggest that treatment options currently approved for NPC disease may be translatable to DHDDS/NUS1 patients.

Keywords:  DHDDS; Niemann-Pick; cholesterol; glycosphingolipids; lysosomal storage disease; miglustat

DOI:  https://doi.org/10.3390/ijms26041471
J Inherit Metab Dis. 2025 Mar;48(2): e70004

"Trafficking Disorders: Phenotypical Similarities and Differences With Other IMDs".

Ángeles García-Cazorla, Eva Morava, Jean-Marie Saudubray.

  Cell trafficking disorders (CTD) are genetic defects in complex molecules and correspond to the largest category of IEM with mutations in more than 370 genes described. They are still poorly recognized as a global entity but rather seen as isolated rare diseases by non-metabolic specialists. Complex lipid metabolism (mostly phospholipids, sphingolipids, and non-mitochondrial fatty acids) is tightly associated with cell trafficking and interactions between organelles at the membrane contact sites. Accordingly, from a clinical point of view CTD presents with multisystem manifestations that may overlap and mimic mitochondrial and other complex molecule disorders such as peroxisomal, lysosomal defects, CDG, or autophagy disorders. The nervous system is especially vulnerable and neurological presentations are prominent, but CTD targets any organ at any age. Interestingly the involvement of the immune system is particularly characteristic of CTD and rarely (or at least little described so far) in other categories of IEM. Most CTD are progressive disorders, except for CDG. They may have "metabolic crises" mimicking disorders of intermediary and energy metabolism for which emergency protocols have been developed. They are generally diagnosed by exome sequencing. Relatively few biomarkers are available.

Keywords:  cell trafficking disorders; haematological symptoms; immune symptoms; lipid metabolism; multisystem symptoms; neurodegeneration; neurodevelopment

DOI:  https://doi.org/10.1002/jimd.70004
J Mol Neurosci. 2025 Feb 25. 75(1): 28

Malformations of Core M3 on α-Dystroglycan Are the Leading Cause of Dystroglycanopathies.

Wessam Sharaf-Eldin.

  Dystroglycanopathies (DGPs) are a group of autosomal recessive neuromuscular diseases with significant clinical and genetic heterogeneity. They originate due to defects in the O-mannosyl glycosylation of α-dystroglycan (α-DG), a prominent linker between the intracellular cytoskeleton and the extracellular matrix (ECM). Fundamentally, such interactions are crucial for the integrity of muscle fibers and neuromuscular synapses, where their defects are mainly associated with muscle and brain dysfunction. To date, biallelic variants in 18 genes have been associated with DGPs, where the underlying cause is still undefined in a significant proportion of patients. Glycosylation of α-DG generates three core motifs where the core M3 is responsible for interaction with the basement membrane. Consistently, all gene defects that corrupt core M3 maturation have been identified as causes of DGPs. POMGNT1 which stimulates the generation of core M1 is also associated with DGPs, as it plays a central role in core M3 processing. Other genes involved in the glycosylation of α-DG seem unrelated to DPGs. The current review illustrates the O-mannosylation pathway of α-DG highlighting the functional properties of related genes and their contribution to the progression of DPGs. Different classes of DPGs are also elaborated characterizing the clinical features of each distinct type and phenotypes associated with each single gene. Finally, current therapeutic approaches with favorable outcomes are addressed. Potential achievements of preclinical and clinical studies would introduce effective curative therapies for this group of disorders in the near future.

Keywords:   POMGNT1 ; Dystroglycanopathies; Neuromuscular diseases; O-Mannosylation; α-Dystroglycan

DOI:  https://doi.org/10.1007/s12031-025-02320-z
Curr Protoc. 2025 Feb;5(2): e70110

Quantification of Glycosaminoglycans in Urine by Isotope Dilution Liquid Chromatography-Electrospray Ionization Tandem Mass Spectrometry.

Haoyue Zhang, James Beasley, Iskren Menkovic, Ashlee Stiles, David S Millington, Sarah P Young.

  Mucopolysaccharidoses (MPSs) are complex lysosomal diseases that result in the accumulation of glycosaminoglycans (GAGs) in urine, blood, and tissues. Lysosomal enzymes responsible for GAG degradation are defective in MPSs. GAGs including chondroitin sulfate (CS), dermatan sulfate (DS), heparan sulfate (HS), and keratan sulfate (KS) are biomarkers for MPSs. This article describes a stable isotope dilution-tandem mass spectrometric method for quantifying CS, DS, and HS in urine samples. The GAGs are methanolyzed to uronic/iduronic acid-N-acetylhexosamine or uronic/iduronic acid-N-glucosamine dimers and mixed with internal standards derived from deuteriomethanolysis of GAG standards. Specific dimers derived from HS, DS, and CS are separated by ultra-performance liquid chromatography (UPLC) and analyzed by electrospray ionization (ESI) tandem mass spectrometry (MS/MS) using selected reaction monitoring for each targeted GAG product and its corresponding internal standard. This UPLC-MS/MS GAG assay is useful for identifying patients with MPS types I, II, III, VI, and VII. © 2025 Wiley Periodicals LLC. Basic Protocol: Urinary GAG analysis by ESI-MS/MS Support Protocol 1: Prepare calibration samples Support Protocol 2: Preparation of stable-isotope-labeled internal standards Support Protocol 3: Preparation of quality controls for GAG analysis in urine Support Protocol 4: Optimization of methanolysis time Support Protocol 5: Measurement of methanolic HCl concentration Support Protocol 6: Preparation of working methanolic HCl solution (1.1 M) Support Protocol 7: Dilution of prepared urine sample.

Keywords:  LC‐ESI‐MS/MS; dermatan sulfate; glycosaminoglycan; heparan sulfate; isotope dilution; mucopolysaccharidosis

DOI:  https://doi.org/10.1002/cpz1.70110
Int J Mol Sci. 2025 Feb 12. pii: 1529. [Epub ahead of print]26(4):

Epalrestat Alleviates Reactive Oxygen Species and Endoplasmic Reticulum Stress by Maintaining Glycosylation in IMS32 Schwann Cells Under Exposure to Galactosemic Conditions.

Hideji Yako, Naoko Niimi, Shizuka Takaku, Junji Yamauchi, Kazunori Sango.

  Aldose reductase (AR), a rate-limiting enzyme in the polyol pathway, mediates the conversion of several substrates, including glucose and galactose. In rodents, galactosemia induced by galactose feeding has been shown to develop peripheral nerve lesions resembling diabetic peripheral neuropathy. However, the mechanisms by which AR-mediated responses elicited Schwan cell lesions under galactosemic conditions remain unresolved. To investigate this, we examined the mechanism of high-galactose-induced damage mediated by AR using AR inhibitors such as ranirestat and epalrestat. The exposure of IMS32 Schwann cells under high-galactose conditions led to galactitol accumulation, the increased production of reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, impaired mitochondrial morphology and membrane potential, decreased glycolysis, and aberrant glycosylation. Under these experimental conditions, ranirestat inhibited intracellular galactitol in a dose-dependent manner, whereas epalrestat failed to inhibit it. Interestingly, even at low concentrations where epalrestat did not inhibit AR activity, it prevented increased ROS production, ER stress, decreased glycolysis, and aberrant RCA120-binding glycosylation; however, no effect of ranirestat on the glycosylation was observed. Epalrestat and ranirestat did not recover mitochondrial morphology. These findings suggest that ER stress is induced by aberrant glycosylation under galactosemic conditions and that epalrestat may be effective in maintaining proper glycosylation in Schwann cells in these conditions.

Keywords:  Schwann cells; aldose reductase; endoplasmic reticulum stress; epalrestat; glycosylation; high-galactose conditions

DOI:  https://doi.org/10.3390/ijms26041529