bims-meglyc 2023-01-22 papers

on Metabolic disorders affecting glycosylation

Issue of 2023–01–22
fiveteen papers selected by
Silvia Radenkovic, Frontiers in Congenital Disorders of Glycosylation Consortium

Inhibiting O-GlcNAcylation impacts p38 and Erk1/2 signaling and perturbs cardiomyocyte hypertrophy.
Immunomodulatory role of glycoRNAs in the brain.
Impact of Hypermannosylation on the Structure and Functionality of the ER and the Golgi Complex.
Cerebral metabolism of glucose and selected glucose transporters in neurodegenerative diseases
Detection of Glycosaminoglycans in Biological Specimens.
Fractionated plasma N-glycan profiling of novel cohort of ATP6AP1-CDG subjects identifies phenotypic association.
A Genetic Approach in the Evaluation of Short Stature.
Nicotinamide adenosine dinucleotide phosphate oxidase-mediated signalling in cardiac remodelling.
The Power of Clinical Diagnosis for Deciphering Complex Genetic Mechanisms in Rare Diseases.
Fructose Metabolism and Its Effect on Glucose-Galactose Malabsorption Patients: A Literature Review.
Nanomedicine based strategies for oligonucleotide traversion across the blood-brain barrier.
MOGS-CDG: quantitative analysis of the diagnostic Glc3 Man tetrasaccharide and clinical spectrum of six new cases.
CRISPR technology: A decade of genome editing is only the beginning.
Human mini-brains for reconstituting central nervous system disorders.
Neurodevelopmental Disorders: Past, Present, and Future.

J Biol Chem. 2023 Jan 12. pii: S0021-9258(23)00039-X. [Epub ahead of print] 102907

Inhibiting O-GlcNAcylation impacts p38 and Erk1/2 signaling and perturbs cardiomyocyte hypertrophy.

Kyriakos N Papanicolaou, Jessica Jung, Deepthi Ashok, Wenxi Zhang, Amir Modaressanavi, Eddie Avila, D Brian Foster, Natasha E Zachara, Brian O'Rourke.

  The dynamic cycling of O-linked N-Acetylglucosamine (O-GlcNAc) on and off Ser/Thr residues of intracellular proteins, termed O-GlcNAcylation, is mediated by the conserved enzymes O-GlcNAc Transferase (OGT) and O-GlcNAcase (OGA). O-GlcNAc cycling is important in homeostatic and stress responses and its perturbation sensitizes the heart to ischemic and other injuries. Despite considerable progress, many molecular pathways impacted by O-GlcNAcylation in the heart remain unclear. The mitogen-activated protein kinase (MAPK) pathway is a central signaling cascade that coordinates developmental, physiological, and pathological responses in the heart. The developmental or adaptive arm of MAPK signaling is primarily mediated by Erk kinases while the pathophysiologic arm is mediated by p38 and Jnk kinases. Here, we examine whether O-GlcNAcylation affects MAPK signaling in cardiac myocytes, focusing on Erk1/2 and p38 in basal and hypertrophic conditions induced by phenylephrine. Using metabolic labeling of glycans coupled with alkyne-azide 'click' chemistry we found that Erk1/2 and p38 are O-GlcNAcylated. Supporting the regulation of p38 by O-GlcNAcylation, the OGT inhibitor, OSMI-1, triggers the phosphorylation of p38, an event that involves the NOX2-Ask1-MKK3/6 signaling axis but also the non-canonical activator Tab1. Additionally, OGT inhibition blocks the phenylephrine-induced phosphorylation of Erk1/2. Consistent with perturbed MAPK signaling, OSMI-1-treated cardiomyocytes have a blunted hypertrophic response to phenylephrine, downregulation of cTnT expression (encoding a key component of the contractile apparatus), and increased expression of maladaptive natriuretic factors Anp and Bnp. Collectively, these studies highlight new roles for O-GlcNAcylation in maintaining a balanced activity of Erk1/2 and p38 MAPKs during hypertrophic growth responses in cardiomyocytes.

Keywords:  Creb; Gata4; Hsp27; Hsp90; Keywords: OGT; MKK3/6; OGA; OSMI; TMG; Tab1

DOI:  https://doi.org/10.1016/j.jbc.2023.102907
J Cereb Blood Flow Metab. 2023 Jan 16. 271678X231151995

Immunomodulatory role of glycoRNAs in the brain.

Anil K Chokkalla, Soomin Jeong, Shruti Subramanian, Raghu Vemuganti.

  Glycosylation of lipids and proteins significantly increases the molecular diversity in the brain. Membrane-localized glycoconjugates facilitate critical neuro-immune interactions. Therefore, glycodysregulation is increasingly recognized as a novel hallmark of various acute and chronic neurological diseases. Although RNAs are heavily modified, they are never thought to be substrates for glycosylation due to their inaccessibility to the glycosylation machinery in the Golgi apparatus. The astonishing discovery of cell surface glycoRNAs opened new avenues for glycomedicine. This review highlighted the key features of GlycoRNAs and further discussed their potential immunomodulatory role in the brain, particularly focusing on post-stroke neuroinflammation.

Keywords:  Epitranscriptomics; glycosylation; microglia; neuroinflammation; stroke

DOI:  https://doi.org/10.1177/0271678X231151995
Biomedicines. 2023 Jan 06. pii: 146. [Epub ahead of print]11(1):

Impact of Hypermannosylation on the Structure and Functionality of the ER and the Golgi Complex.

Patricia Franzka, Svenja Caren Schüler, Takfarinas Kentache, Robert Storm, Andrea Bock, Istvan Katona, Joachim Weis, Katrin Buder, Christoph Kaether, Christian A Hübner.

  Proteins of the secretory pathway undergo glycosylation in the endoplasmic reticulum (ER) and the Golgi apparatus. Altered protein glycosylation can manifest in serious, sometimes fatal malfunctions. We recently showed that mutations in GDP-mannose pyrophosphorylase A (GMPPA) can cause a syndrome characterized by alacrima, achalasia, mental retardation, and myopathic alterations (AAMR syndrome). GMPPA acts as a feedback inhibitor of GDP-mannose pyrophosphorylase B (GMPPB), which provides GDP-mannose as a substrate for protein glycosylation. Loss of GMPPA thus enhances the incorporation of mannose into glycochains of various proteins, including α-dystroglycan (α-DG), a protein that links the extracellular matrix with the cytoskeleton. Here, we further characterized the consequences of loss of GMPPA for the secretory pathway. This includes a fragmentation of the Golgi apparatus, which comes along with a regulation of the abundance of several ER- and Golgi-resident proteins. We further show that the activity of the Golgi-associated endoprotease furin is reduced. Moreover, the fraction of α-DG, which is retained in the ER, is increased. Notably, WT cells cultured at a high mannose concentration display similar changes with increased retention of α-DG, altered structure of the Golgi apparatus, and a decrease in furin activity. In summary, our data underline the importance of a balanced mannose homeostasis for the secretory pathway.

Keywords:  Golgi network; endoplasmic reticulum; mannosylation

DOI:  https://doi.org/10.3390/biomedicines11010146
Postepy Biochem. 2022 12 31. 68(4): 375-380

Cerebral metabolism of glucose and selected glucose transporters in neurodegenerative diseases

Natalia Białoń, Michał Trzęsicki, Mikołaj Górka, Krzysztof Suszyński, Dariusz Górka.

Cerebral glucose metabolism is an issue of researchers’ interest for a long time. Disturbed transport and metabolism of glucose in the brain lead to development of numerous neurological pathologies. Recently, a significant correlation between perturbed cerebral glucose metabolism and development of neurodegenerative diseases has been shown. Glucose, a monosaccharide, is the main source of energy for brain cells. Brain is the organ which is the most sensitive to changes in blood glucose level. Perturbed glucose transport leads to disorders of the central glucose metabolism. Neurodegenerative diseases are defined in the literature as progressive and irreversible degeneration of nerve tissue, causing cell death as a result of degenerative processes. The aim of this article is to discuss the physiology and the role of selected glucose transporters in the development of neurodegenerative diseases: expression of selected GLUT1 and GLUT3 transporters in Alzheimer's and Huntington's diseases. Understanding of the cerebral glucose metabolism may be a crucial factor in fight with central nervous system diseases.

DOI: https://doi.org/10.18388/pb.2021_463
Methods Mol Biol. 2023 ;2619 3-24

Detection of Glycosaminoglycans in Biological Specimens.

Shaukat A Khan, F N U Nidhi, Paige C Amendum, Shunji Tomatsu.

  Proteoglycans (PGs) are macromolecules formed by a protein backbone to which one or more glycosaminoglycan (GAG) side chains are covalently attached. Most PGs are present in connective tissues, cell surfaces, and intracellular compartments. The major biological function of PGs derives from the GAG component of the molecule, which is involved in cell growth and proliferation, embryogenesis, maintenance of tissue hydration, and interactions of the cells via receptors. PGs are categorized into four groups based on their cellular and subcellular localization, including cell surfaces and extracellular, intracellular, and pericellular locations. GAGs are a crucial component of PGs involved in various physiological and pathological processes. GAGs also serve as biomarkers of metabolic diseases such as mucopolysaccharidoses and mucolipidoses. Detection of specific GAGs in various biological fluids helps manage various genetic metabolic disorders before it causes irreversible damage to the patient (Amendum et al., Diagnostics (Basel) 11(9):1563, 2021). There are several methods for detecting GAGs; this chapter focuses on measuring GAGs using enzyme-linked immunosorbent assay, liquid chromatographic tandem mass spectrometry, and automated high-throughput mass spectrometry.

Keywords:  ELISA; Glycosaminoglycans; High throughput; LC-MS/MS; Proteoglycans

DOI:  https://doi.org/10.1007/978-1-0716-2946-8_1
J Inherit Metab Dis. 2023 Jan 18.

Fractionated plasma N-glycan profiling of novel cohort of ATP6AP1-CDG subjects identifies phenotypic association.

Hana Alharbi, Earnest James Paul Daniel, Jenny Thies, Irene Chang, Dana L Goldner, Bobby G Ng, Peter Witters, Amal Aqul, Frances Velez-Bartolomei, Gregory M Enns, Evelyn Hsu, Elizabeth Kichula, Esther Lee, Charles Lourenco, Sheri A Poskanzer, Sara Rasmussen, Katelyn Saarela, YunZu M Wang, Kimiyo M Raymond, Matthew J Schultz, Hudson H Freeze, Christina Lam, Andrew C Edmondson, Miao He.

  ATP6AP1-CDG is an X-linked disorder typically characterized by hepatopathy, immunodeficiency and an abnormal type II transferrin glycosylation pattern. Here, we present eleven new patients and clinical updates with biochemical characterization on one previously reported patient. We also document intrafamilial phenotypic variability and atypical presentations, expanding the symptomatology of ATP6AP1-CDG to include dystonia, hepatocellular carcinoma and lysosomal abnormalities on hepatic histology. Three of our subjects received successful liver transplantation. We performed N-glycan profiling of total and fractionated plasma proteins for six patients and show associations with varying phenotypes, demonstrating potential diagnostic and prognostic value of fractionated N-glycan profiles. The aberrant N-linked glycosylation in purified transferrin and remaining plasma glycoprotein fractions normalized in one patient post hepatic transplant, while the increases of Man4GlcNAc2 and Man5GlcNAc2 in purified immunoglobulins persisted. Interestingly, in the single patient with isolated immune deficiency phenotype, elevated high-mannose glycans were detected on purified immunoglobulins without glycosylation abnormalities on transferrin or the remaining plasma glycoprotein fractions. Given the diverse and often tissue specific clinical presentations and the need of clinical management post hepatic transplant in ATP6AP1-CDG patients, these results demonstrate that fractionated plasma N-glycan profiling could be a valuable tool in diagnosis and disease monitoring. This article is protected by copyright. All rights reserved.

Keywords:  ATP6AP1-CDG; congenital disorder of glycosylation; dystonia; hyperkinetic movement; immunodeficiency; liver failure

DOI:  https://doi.org/10.1002/jimd.12589
Eurasian J Med. 2022 Dec;54(Suppl1): 179-186

A Genetic Approach in the Evaluation of Short Stature.

Ayberk Turkyilmaz, Ayse Sena Donmez, Atilla Cayir.

Short stature is considered a condition in which the height is 2 standard deviations below the mean height of a given age, sex, and population group. Human height is a polygenic and heterogeneous characteristic, and its heritability is reported to be approximately 80%. More than 600 variants associated with human growth were detected in the genome-wide association studies. Rare and common variants concurrently affect human height. The rare variations that play a role in human height determination and have a strong impact on protein functions lead to monogenic short stature phenotypes, which are a highly heterogeneous group. With rapidly developing technologies in the last decade, molecular genetic tests have begun to be used widely in clinical genetics, and thus, the genetic etiology of several rare diseases has been elucidated. Identifying the genetic etiology underlying idiopathic short stature which represents phenotypically heterogeneous group of diseases ranging from isolated short stature to severe and syndromic short stature has promoted the understanding of the genetic regulation of growth plate and longitudinal bone growth. In cases of short stature, definite molecular diagnosis based on genetic evaluation enables the patient and family to receive genetic counseling on the natural course of the disease, prognosis, genetic basis, and recurrence risk. The determination of the genetic etiology in growth disorders is essential for the development of novel targeted therapies and crucial in the development of mutation-specific treatments in the future.

DOI: https://doi.org/10.5152/eurasianjmed.2022.22171
Antioxid Redox Signal. 2023 Jan 19.

Nicotinamide adenosine dinucleotide phosphate oxidase-mediated signalling in cardiac remodelling.

Asjad Visnagri, Rafael Oexner, Katarzyna Kmiotek-Wasylewska, Min Zhang, Anna Zoccarato, Ajay Shah.

SIGNIFICANCE: Reactive oxygen species (ROS) play a key role in the pathogenesis of cardiac remodelling and the subsequent progression to heart failure (HF). Nicotinamide adenosine dinucleotide phosphate (NADPH) oxidases (NOXs) are one of the major sources of ROS and are expressed in different heart cell types including cardiomyocytes, endothelial cells, fibroblasts and inflammatory cells.
RECENT ADVANCES: NOX-derived ROS are usually produced in a regulated and spatially confined fashion and typically linked to specific signalling. The two main cardiac isoforms, namely NOX2 and NOX4, possess different biochemical and (patho)physiological properties and exert distinct effects on the cardiac phenotype in many settings. Recent work has defined important cell-specific effects of NOX2 that contribute to pathological cardiac remodelling and dysfunction. NOX4 on the other hand may exert protective effects by stimulating adaptive stress responses, with recent data showing that NOX4-mediated signalling regulates transcription and metabolism in the heart.
CRITICAL ISSUES: The inhibition of NOX2 appears to be a very promising therapeutic target to ameliorate pathological cardiac remodelling. If the beneficial effects of NOX4 can be enhanced, this might be a unique approach to boosting adaptive responses and thereby impact on cell survival, activation, contractility and growth.
FUTURE DIRECTIONS: Increasing knowledge regarding the intricacies of NOX-mediated signalling may yield tractable therapeutic targets in contrast to the non-specific targeting of oxidative stress.

DOI: https://doi.org/10.1089/ars.2022.0176
Genes (Basel). 2023 Jan 12. pii: 196. [Epub ahead of print]14(1):

The Power of Clinical Diagnosis for Deciphering Complex Genetic Mechanisms in Rare Diseases.

Li Shu, Tatiana Maroilley, Maja Tarailo-Graovac.

  Complex genetic disease mechanisms, such as structural or non-coding variants, currently pose a substantial difficulty in frontline diagnostic tests. They thus may account for most unsolved rare disease patients regardless of the clinical phenotype. However, the clinical diagnosis can narrow the genetic focus to just a couple of genes for patients with well-established syndromes defined by prominent physical and/or unique biochemical phenotypes, allowing deeper analyses to consider complex genetic origin. Then, clinical-diagnosis-driven genome sequencing strategies may expedite the development of testing and analytical methods to account for complex disease mechanisms as well as to advance functional assays for the confirmation of complex variants, clinical management, and the development of new therapies.

Keywords:  clinical diagnosis; complex mechanism; non-coding variants; rare disease; structural variants

DOI:  https://doi.org/10.3390/genes14010196
Diagnostics (Basel). 2023 Jan 12. pii: 294. [Epub ahead of print]13(2):

Fructose Metabolism and Its Effect on Glucose-Galactose Malabsorption Patients: A Literature Review.

Nawaf W Alruwaili, Fahad Alshdayed.

  Glucose-galactose malabsorption is a rare inherited autosomal recessive genetic defect. A mutation in the glucose sodium-dependent transporter-1 gene will alter the transportation and absorption of glucose and galactose in the intestine. The defect in the SGLT-1 leads to unabsorbed galactose, glucose, and sodium, which stay in the intestine, leading to dehydration and hyperosmotic diarrhea. Often, glucose-galactose malabsorption patients are highly dependent on fructose, their primary source of carbohydrates. This study aims to investigate all published studies on congenital glucose-galactose malabsorption and fructose malabsorption. One hundred published studies were assessed for eligibility in this study, and thirteen studies were identified and reviewed. Studies showed that high fructose consumption has many health effects and could generate life-threatening complications. None of the published studies included in this review discussed or specified the side effects of fructose consumption as a primary source of carbohydrates in congenital glucose-galactose malabsorption patients.

Keywords:  SGLT1; SLC5A1; autosomal recessive genetic defects; fructose malabsorption; glucose–galactose malabsorption; metabolic syndrome

DOI:  https://doi.org/10.3390/diagnostics13020294
J Control Release. 2023 Jan 14. pii: S0168-3659(23)00040-8. [Epub ahead of print]

Nanomedicine based strategies for oligonucleotide traversion across the blood-brain barrier.

Etikala Amulya, Anupama Sikder, Ganesh Vambhurkar, Saurabh Shah, Dharmendra Kumar Khatri, Rajeev Singh Raghuvanshi, Shashi Bala Singh, Saurabh Srivastava.

  Neurological disorders are considered the most prominent cause of disability worldwide. The major hurdle in the management of neurological disorders is the existence of the blood-brain barrier (BBB), which hinders the entry of several therapeutic moieties. In recent years, oligonucleotides have gained tremendous attention for their target specificity, diminished dose and adverse effects, thereby halting disease progression. However, enzymatic degradation, rapid clearance, limited circulation and availability at the bio-active site, etc., limit its clinical translation. Nanomedicine has opened up a breadth of opportunities in the delivery of oligonucleotides across the BBB. This review addresses the pitfalls associated with oligonucleotide delivery in traversing the BBB via nanotherapeutics for the management of brain disorders. Regulatory perspectives pertaining to hastening the clinical translation of oligonucleotide-loaded nanocarriers for brain delivery have been highlighted.

Keywords:  Blood–brain barrier; Central nervous system; Nanocarriers; Neurological disorders; Oligonucleotides; Regulatory perspectives

DOI:  https://doi.org/10.1016/j.jconrel.2023.01.031
J Inherit Metab Dis. 2023 Jan 18.

MOGS-CDG: quantitative analysis of the diagnostic Glc3 Man tetrasaccharide and clinical spectrum of six new cases.

Merel A Post, Isis de Wit, Fokje S M Zijlstra, Udo F H Engelke, Arno van Rooij, John Christodoulou, Tiong Yang Tan, Anna Le Fevre, Danqun Jin, Joy Yaplito-Lee, Beom Hee Lee, Karen J Low, Andrew A Mallick, Katrin Õunap, James Pitt, William Reardon, Mari-Anne Vals, Saskia B Wortmann, Hans J C T Wessels, Melissa Bärenfänger, Clara D M van Karnebeek, Dirk J Lefeber.

  Congenital disorders of glycosylation (CDG) are a clinically and biochemically heterogenous subgroup of inherited metabolic disorders. Most CDG with abnormal N-glycosylation can be detected by transferrin screening, however, MOGS-CDG escapes this routine screening. Combined with the clinical heterogeneity of reported cases, diagnosing MOGS-CDG can be challenging. Here, we clinically characterize ten MOGS-CDG cases, six previously unreported individuals, showing a phenotype characterized by dysmorphic features, global developmental delay, muscular hypotonia, and seizures in all patients and in a minority vision problems and hypogammaglobulinemia. Glycomics confirmed accumulation of Glc3 Man7 GlcNAc2 glycans in plasma. For quantification of the diagnostic Glcα1-3Glcα1-3Glcα1-2Man tetrasaccharide in urine, we developed and validated a liquid chromatography-mass spectrometry method of 2-aminobenzoic acid (2AA) labeled urinary glycans. As an internal standard, isotopically labeled 13 C6 -2AA Glc3 Man was used, while labeling efficiency was controlled by use of 12 C6 -2AA and 13 C6 - 2AA labeled laminaritetraose. Recovery, linearity, intra- inter coefficients of variability (CV %) of these labeled compounds were determined. Furthermore Glc3 Man was specifically identified by retention time matching against authentic MOGS-CDG urine (factor accumulation) and Pompe urine. Glc3 Man was increased in all six analyzed cases, ranging from 34,1- 618,0 μmol/mmol creatinine (reference <5 μmol). In short, MOGS-CDG has a broad manifestation of symptoms but can be diagnosed and more importantly quantified with the use of a targeted method for the urinary excretion of the Glc3 Man biomarker. This article is protected by copyright. All rights reserved.

Keywords:  MOGS-CDG; biomarker; multisystem; tetraglucoside; urine oligosaccharide

DOI:  https://doi.org/10.1002/jimd.12588
Science. 2023 Jan 20. 379(6629): eadd8643

CRISPR technology: A decade of genome editing is only the beginning.

Joy Y Wang, Jennifer A Doudna.

The advent of clustered regularly interspaced short palindromic repeat (CRISPR) genome editing, coupled with advances in computing and imaging capabilities, has initiated a new era in which genetic diseases and individual disease susceptibilities are both predictable and actionable. Likewise, genes responsible for plant traits can be identified and altered quickly, transforming the pace of agricultural research and plant breeding. In this Review, we discuss the current state of CRISPR-mediated genetic manipulation in human cells, animals, and plants along with relevant successes and challenges and present a roadmap for the future of this technology.

DOI: https://doi.org/10.1126/science.add8643
Lab Chip. 2023 Jan 16.

Human mini-brains for reconstituting central nervous system disorders.

You Jung Kang, Yingqi Xue, Jae Hee Shin, Hansang Cho.

Neurological disorders in the central nervous system (CNS) are progressive and irreversible diseases leading to devastating impacts on patients' life as they cause cognitive impairment, dementia, and even loss of essential body functions. The development of effective medicines curing CNS disorders is, however, one of the most ambitious challenges due to the extremely complex functions and structures of the human brain. In this regard, there are unmet needs to develop simplified but physiopathologically-relevant brain models. Recent advances in the microfluidic techniques allow multicellular culture forming miniaturized 3D human brains by aligning parts of brain regions with specific cells serving suitable functions. In this review, we overview designs and strategies of microfluidics-based human mini-brains for reconstituting CNS disorders, particularly Alzheimer's disease (AD), Parkinson's disease (PD), traumatic brain injury (TBI), vascular dementia (VD), and environmental risk factor-driven dementia (ERFD). Afterward, the applications of the mini-brains in the area of medical science are introduced in terms of the clarification of pathogenic mechanisms and identification of promising biomarkers. We also present expanded model systems ranging from the CNS to CNS-connecting organ axes to study the entry pathways of pathological risk factors into the brain. Lastly, the advantages and potential challenges of current model systems are addressed with future perspectives.

DOI: https://doi.org/10.1039/d2lc00897a
Children (Basel). 2022 Dec 24. pii: 31. [Epub ahead of print]10(1):

Neurodevelopmental Disorders: Past, Present, and Future.

Elisa Cainelli, Patrizia Bisiacchi.

  Recent decades have seen a dramatic increase in neurodevelopmental disorders and the attention paid to them. Since their emergence in the not-so-distant past, some neurodevelopmental disorders have undergone considerable redefinition and, beginning in the 21st century, there has been a massive increase in research. In this paper, we briefly review the history of some of them, address some of the issues that characterize their current management and relationship with neurological pathologies, and share some insights for the future.

Keywords:  ADHD; autism; cognition; neuropsychology; specific learning disabilities

DOI:  https://doi.org/10.3390/children10010031