bims-meglyc 2023-08-13 papers

on Metabolic disorders affecting glycosylation

Issue of 2023–08–13
eight papers selected by
Silvia Radenkovic, Frontiers in Congenital Disorders of Glycosylation Consortium

The multifaceted roles of the brain glycogen.
Highlighting rare disease research with a GENETICS and G3 series on genetic models of rare diseases.
Highlighting rare disease research with a GENETICS and G3 series on genetic models of rare diseases.
The glycosylation defect in solute carrier SLC35A2/SLC35A3 double knockout cells is rescued by SLC35A2-SLC35A3 and SLC35A3-SLC35A2 hybrids.
Association between acute complications in PMM2-CDG patients and haemostasis anomalies: Data from a multicentric study and suggestions for acute management.
Sialic acid: an attractive biomarker with promising biomedical applications.
The role of mitochondria in myocardial damage caused by energy metabolism disorders: From mechanisms to therapeutics.
Enrichment analysis of phenotypic data for drug repurposing in rare diseases.

J Neurochem. 2023 Aug 09.

The multifaceted roles of the brain glycogen.

Kia H Markussen, Manuela Corti, Barry J Byrne, Craig W Vander Kooi, Ramon C Sun, Matthew S Gentry.

  Glycogen is a biologically essential macromolecule that is directly involved in multiple human diseases. While its primary role in carbohydrate storage and energy metabolism in the liver and muscle is well characterized, recent research has highlighted critical metabolic and non-metabolic roles for glycogen in the brain. In this review, the emerging roles of glycogen homeostasis in the healthy and diseased brain are discussed with a focus on advancing our understanding of the role of glycogen in the brain. Innovative technologies that have led to novel insights into glycogen functions are detailed. Key insights into how cellular localization impacts neuronal and glial function are discussed. Perturbed glycogen functions are observed in multiple disorders of the brain, including where it serves as a disease driver in the emerging category of neurological glycogen storage diseases (n-GSDs). n-GSDs include Lafora disease (LD), adult polyglucosan body disease (APBD), Cori disease, Glucose transporter type 1 deficiency syndrome (G1D), GSD0b, and late-onset Pompe disease (PD). They are neurogenetic disorders characterized by aberrant glycogen which results in devastating neurological and systemic symptoms. In the most severe cases, rapid neurodegeneration coupled with dementia results in death soon after diagnosis. Finally, we discuss current treatment strategies that are currently being developed and have the potential to be of great benefit to patients with n-GSD. Taken together, novel technologies and biological insights have resulted in a renaissance in brain glycogen that dramatically advanced our understanding of both biology and disease. Future studies are needed to expand our understanding and the multifaceted roles of glycogen and effectively apply these insights to human disease.

Keywords:  N-linked glycosylation; brain metabolism; congenital disorders of glycosylation; epilepsy; glycogen; glycogen storage disease

DOI:  https://doi.org/10.1111/jnc.15926
G3 (Bethesda). 2023 Aug 09. pii: jkad144. [Epub ahead of print]13(8):

Highlighting rare disease research with a GENETICS and G3 series on genetic models of rare diseases.

Philip Hieter, Brenda Andrews, Douglas Fowler, Hugo Bellen.

DOI: https://doi.org/10.1093/g3journal/jkad144
Genetics. 2023 Aug 09. pii: iyad121. [Epub ahead of print]224(4):

Highlighting rare disease research with a GENETICS and G3 series on genetic models of rare diseases.

Philip Hieter, Brenda Andrews, Douglas Fowler, Hugo Bellen.

DOI: https://doi.org/10.1093/genetics/iyad121
FEBS Lett. 2023 Aug 08.

The glycosylation defect in solute carrier SLC35A2/SLC35A3 double knockout cells is rescued by SLC35A2-SLC35A3 and SLC35A3-SLC35A2 hybrids.

Wojciech Wiertelak, Artem Pavlovskyi, Dorota Maszczak-Seneczko, Bożena Szulc, Mariusz Olczak.

  SLC35A2 and SLC35A3 are homologous proteins with postulated nucleotide sugar transporting activities. Unlike SLC35A2, whose specificity for UDP-Gal is well established, the UDP-GlcNAc transporting activity initially attributed to SLC35A3 has recently been put into question. In this study, we constructed two hybrid proteins (SLC35A2-SLC35A3 and SLC35A3-SLC35A2) and expressed them in a previously generated SLC35A2/SLC35A3 double knockout HEK293T cell line. Our idea was to force equivalent stoichiometry of the two proteins in the cells in order to reproduce the behavior of the SLC35A2/SLC35A3 complexes in the Golgi membrane. The hybrid proteins were able to fully restore glycosylation in the double knockout. In contrast, the expression of SLC35A3 alone in these cells improved galactosylation only to a limited extent. Our study shows that the proper glycosylation requires a balanced cooperation between SLC35A2 and SLC35A3.

Keywords:  Golgi apparatus; N-glycans; UDP-Gal; UDP-GlcNAc; hybrid proteins; mucin-type O-glycans

DOI:  https://doi.org/10.1002/1873-3468.14714
Mol Genet Metab. 2023 Jul 31. pii: S1096-7192(23)00304-9. [Epub ahead of print]140(3): 107674

Association between acute complications in PMM2-CDG patients and haemostasis anomalies: Data from a multicentric study and suggestions for acute management.

Camille Wicker, Charles-Joris Roux, Louise Goujon, Yvan de Feraudy, Marie Hully, Anais Brassier, Claire-Marine Bérat, Nicole Chemaly, Arnaud Wiedemann, Lena Damaj, Marie-Thérèse Abi-Warde, Dries Dobbelaere, Agathe Roubertie, Aline Cano, Alina Arion, Anna Kaminska, Sabrina Da Costa, Arnaud Bruneel, Sandrine Vuillaumier-Barrot, Nathalie Boddaert, Tiffany Pascreau, Delphine Borgel, Manoelle Kossorotoff, Annie Harroche, P de Lonlay.

   OBJECTIVES: Patients with PMM2-CDG develop acute events (stroke-like episodes (SLEs), thromboses, haemorrhages, seizures, migraines) associated with both clotting factors (factor XI) and coagulation inhibitors (antithrombin, protein C and protein S) deficiencies. The aim of the study was to correlate acute events to haemostasis and propose practical guidelines.
METHODS: In this multicentric retrospective study, we evaluated clinical, radiological, haemostasis and electroencephalography data for PMM2-CDG patients hospitalized for acute events. Cerebral events were classified as thrombosis, haemorrhage, SLE, or "stroke mimic" (SM: normal brain imaging or evoking a migraine).
RESULTS: Thirteen patients had a total of 31 acute episodes: 27 cerebral events with 7 SLEs, 4 venous thromboses, 4 haemorrhages (3 associated with thrombosis), 15 SMs at a mean age of 7.7 years; 4 non-cerebral thromboses, one of which included bleeding. A trigger was frequently involved (infection, head trauma). Although sometimes normal at baseline state, factor XI, antithrombin and protein C levels decreased during these episodes. No correlation between haemostasis anomalies and type of acute event was found.
DISCUSSION: Acute events in PMM2-CDG are not negligible and are associated with haemostasis anomalies. An emergency protocol is proposed for their prevention and treatment (https://www.filiere-g2m.fr/urgences). For cerebral events, brain Magnetic Resonance Imaging with perfusion weight imaging and diffusion sequences, electroencephalogram and haemostasis protein levels guide the treatment: anticoagulation, antithrombin or fresh frozen plasma supplementation, antiepileptic therapy. Preventing bleeding and thrombosis is required in cases of surgery, prolonged immobilization, hormone replacement therapy.
CONCLUSION: Acute events in PMM2-CDG are associated with abnormal haemostasis, requiring practical guidance.

Keywords:  Coagulation; Emergency protocol; Haemorrhages; PMM2-CDG; Stroke-like episodes; Thrombosis

DOI:  https://doi.org/10.1016/j.ymgme.2023.107674
Asian Biomed (Res Rev News). 2022 Aug;16(4): 153-167

Sialic acid: an attractive biomarker with promising biomedical applications.

Aida Doostkam, Leila Malekmakan, Alireza Hosseinpour, Sahar Janfeshan, Jamshid Roozbeh, Fatemeh Masjedi.

  This broad, narrative review highlights the roles of sialic acids as acidic sugars found on cellular membranes. The role of sialic acids in cellular communication and development has been well established. Recently, attention has turned to the fundamental role of sialic acids in many diseases, including viral infections, cardiovascular diseases, neurological disorders, diabetic nephropathy, and malignancies. Sialic acid may be a target for developing new drugs to treat various cancers and inflammatory processes. We recommend the routine measurement of serum sialic acid as a sensitive inflammatory marker in various diseases.

Keywords:  cardiovascular diseases; diabetic nephropathies; molecular targeted therapy; neoplasms; neuraminic acids; sialic acid; virus diseases

DOI:  https://doi.org/10.2478/abm-2022-0020
Free Radic Biol Med. 2023 Aug 09. pii: S0891-5849(23)00581-6. [Epub ahead of print]

The role of mitochondria in myocardial damage caused by energy metabolism disorders: From mechanisms to therapeutics.

Ao-Lin Li, Lu Lian, Xin-Nong Chen, Wen-Hui Cai, Xin-Biao Fan, Ya-Jie Fan, Ting-Ting Li, Ying-Yu Xie, Jun-Ping Zhang.

  Myocardial damage is the most serious pathological consequence of cardiovascular diseases and an important reason for their high mortality. In recent years, because of the high prevalence of systemic energy metabolism disorders (e.g., obesity, diabetes mellitus, and metabolic syndrome), complications of myocardial damage caused by these disorders have attracted widespread attention. Energy metabolism disorders are independent of traditional injury-related risk factors, such as ischemia, hypoxia, trauma, and infection. An imbalance of myocardial metabolic flexibility and myocardial energy depletion are usually the initial changes of myocardial injury caused by energy metabolism disorders, and abnormal morphology and functional destruction of the mitochondria are their important features. Specifically, mitochondria are the centers of energy metabolism, and recent evidence has shown that decreased mitochondrial function, caused by an imbalance in mitochondrial quality control, may play a key role in myocardial injury caused by energy metabolism disorders. Under chronic energy stress, mitochondria undergo pathological fission, while mitophagy, mitochondrial fusion, and biogenesis are inhibited, and mitochondrial protein balance and transfer are disturbed, resulting in the accumulation of nonfunctional and damaged mitochondria. Consequently, damaged mitochondria lead to myocardial energy depletion and the accumulation of large amounts of reactive oxygen species, further aggravating the imbalance in mitochondrial quality control and forming a vicious cycle. In addition, impaired mitochondria coordinate calcium homeostasis imbalance, and epigenetic alterations participate in the pathogenesis of myocardial damage. These pathological changes induce rapid progression of myocardial damage, eventually leading to heart failure or sudden cardiac death. To intervene more specifically in the myocardial damage caused by metabolic disorders, we need to understand the specific role of mitochondria in this context in detail. Accordingly, promising therapeutic strategies have been proposed. We also summarize the existing therapeutic strategies to provide a reference for clinical treatment and developing new therapies.

Keywords:  Calcium homeostasis; Energy metabolism; Epigenetics; Mitochondria; Mitochondrial quality control; Myocardial damage; Oxidative stress; Therapy

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.08.009
Front Pharmacol. 2023 ;14 1128562

Enrichment analysis of phenotypic data for drug repurposing in rare diseases.

Alberto Ambesi-Impiombato, Kimberly Cox, Sylvie Ramboz, Daniela Brunner, Mukesh Bansal, Emer Leahy.

  Drug-induced Behavioral Signature Analysis (DBSA), is a machine learning (ML) method for in silico screening of compounds, inspired by analytical methods quantifying gene enrichment in genomic analyses. When applied to behavioral data it can identify drugs that can potentially reverse in vivo behavioral symptoms in animal models of human disease and suggest new hypotheses for drug discovery and repurposing. We present a proof-of-concept study aiming to assess Drug-induced Behavioral Signature Analysis (DBSA) as a systematic approach for drug discovery for rare disorders. We applied Drug-induced Behavioral Signature Analysis to high-content behavioral data obtained with SmartCube®, an automated in vivo phenotyping platform. The therapeutic potential of several dozen approved drugs was assessed for phenotypic reversal of the behavioral profile of a Huntington's Disease (HD) murine model, the Q175 heterozygous knock-in mice. The in silico Drug-induced Behavioral Signature Analysis predictions were enriched for drugs known to be effective in the symptomatic treatment of Huntington's Disease, including bupropion, modafinil, methylphenidate, and several SSRIs, as well as the atypical antidepressant tianeptine. To validate the method, we tested acute and chronic effects of tianeptine (20 mg/kg, i. p.) in vivo, using Q175 mice and wild type controls. In both experiments, tianeptine significantly rescued the behavioral phenotype assessed with the SmartCube® platform. Our target-agnostic method thus showed promise for identification of symptomatic relief treatments for rare disorders, providing an alternative method for hypothesis generation and drug discovery for disorders with huge disease burden and unmet medical needs.

Keywords:  animal models; computational method; drug discovery; huntington (disease); phenotypic screening; smartcube; tianeptine

DOI:  https://doi.org/10.3389/fphar.2023.1128562