bims-meglyc 2023-12-24 papers

on Metabolic disorders affecting glycosylation

Issue of 2023–12–24
seven papers selected by
Silvia Radenkovic, Frontiers in Congenital Disorders of Glycosylation Consortium

AAV9-based PMM2 gene replacement augments PMM2 expression and improves glycosylation in primary fibroblasts of patients with phosphomannomutase 2 deficiency (PMM2-CDG).
Drosophila models of PIGA-CDG mirror patient phenotypes.
Protein O-GlcNAcylation: The sweet hub in liver metabolic flexibility from a (patho)physiological perspective.
O-GlcNAcylation: cellular physiology and therapeutic target for human diseases.
Pre-implantation Genetic Testing in Inherited Metabolic Diseases? Stateof- the-art and current challenges.
Untangling adaptive functioning of PMM2-CDG across age and its impact on parental stress: a cross-sectional study.
New insights into the role of GSK-3β in the brain: from neurodegenerative disease to tumorigenesis.

Mol Genet Metab Rep. 2024 Mar;38 101035

AAV9-based PMM2 gene replacement augments PMM2 expression and improves glycosylation in primary fibroblasts of patients with phosphomannomutase 2 deficiency (PMM2-CDG).

M Zhong, B Balakrishnan, A J Guo, K Lai.

  Inherited deficiency of phosphomannomutase 2 (PMM2) (aka PMM2-CDG) is the most common congenital disorders of glycosylation (CDG) and has no cure. With debilitating morbidity and significant mortality, it is imperative to explore novel, safe, and effective therapies for the disease. Our Proof-of-Concept study showed that AAV9-PMM2 infection of patient fibroblasts augmented PMM2 expression and improved glycosylation. Thus, AAV9-PMM2 gene replacement is a promising therapeutic strategy for PMM2-CDG patients.

Keywords:  AAV9 gene replacement therapy; Congenital disorders of glycosylation; Inherited phosphomannomutase 2 deficiency (PMM2-CDG); Primary fibroblast cell model

DOI:  https://doi.org/10.1016/j.ymgmr.2023.101035
G3 (Bethesda). 2023 Dec 20. pii: jkad291. [Epub ahead of print]

Drosophila models of PIGA-CDG mirror patient phenotypes.

Holly J Thorpe, Katie G Owings, Miriam C Aziz, Madelyn Haller, Emily Coelho, Clement Y Chow.

  Mutations in the phosphatidylinositol glycan biosynthesis class A (PIGA) gene cause a rare, X-linked recessive congenital disorder of glycosylation (CDG). PIGA-CDG is characterized by seizures, intellectual and developmental delay, and congenital malformations. The PIGA gene encodes an enzyme involved in the first step of GPI anchor biosynthesis. There are over 100 GPI anchored proteins that attach to the cell surface and are involved in cell signaling, immunity, and adhesion. Little is known about the pathophysiology of PIGA-CDG. Here we describe the first Drosophila model of PIGA-CDG and demonstrate that loss of PIG-A function in Drosophila accurately models the human disease. As expected, complete loss of PIG-A function is larval lethal. Heterozygous null animals appear healthy, but when challenged, have a seizure phenotype similar to what is observed in patients. To identify the cell-type specific contributions to disease, we generated neuron- and glia-specific knockdown of PIG-A. Neuron-specific knockdown resulted in reduced lifespan and a number of neurological phenotypes, but no seizure phenotype. Glia-knockdown also reduced lifespan and, notably, resulted in a very strong seizure phenotype. RNAseq analyses demonstrated that there are fundamentally different molecular processes that are disrupted when PIG-A function is eliminated in different cell types. In particular, loss of PIG-A in neurons resulted in upregulation of glycolysis, but loss of PIG-A in glia resulted in upregulation of protein translation machinery. Here we demonstrate that Drosophila is a good model of PIGA-CDG and provide new data resources for future study of PIGA-CDG and other GPI anchor disorders.

Keywords:   Drosophila ; Epilepsy; GPI anchor; PIGA; Rare disease

DOI:  https://doi.org/10.1093/g3journal/jkad291
Liver Int. 2023 Dec 18.

Protein O-GlcNAcylation: The sweet hub in liver metabolic flexibility from a (patho)physiological perspective.

Ya-Jie Hu, Xu Zhang, Hong-Ming Lv, Yang Liu, Shi-Ze Li.

  O-GlcNAcylation is a dynamic, reversible and atypical O-glycosylation that regulates various cellular physiological processes via conformation, stabilisation, localisation, chaperone interaction or activity of target proteins. The O-GlcNAcylation cycle is precisely controlled by collaboration between O-GlcNAc transferase and O-GlcNAcase. Uridine-diphosphate-N-acetylglucosamine, the sole donor of O-GlcNAcylation produced by the hexosamine biosynthesis pathway, is controlled by the input of glucose, glutamine, acetyl coenzyme A and uridine triphosphate, making it a sensor of the fluctuation of molecules, making O-GlcNAcylation a pivotal nutrient sensor for the metabolism of carbohydrates, amino acids, lipids and nucleotides. O-GlcNAcylation, particularly prevalent in liver, is the core hub for controlling systemic glucose homeostasis due to its nutritional sensitivity and precise spatiotemporal regulation of insulin signal transduction. The pathology of various liver diseases has highlighted hepatic metabolic disorder and dysfunction, and abnormal O-GlcNAcylation also plays a specific pathological role in these processes. Therefore, this review describes the unique features of O-GlcNAcylation and its dynamic homeostasis maintenance. Additionally, it explains the underlying nutritional sensitivity of O-GlcNAcylation and discusses its mechanism of spatiotemporal modulation of insulin signal transduction and liver metabolic homeostasis during the fasting and feeding cycle. This review emphasises the pathophysiological implications of O-GlcNAcylation in nonalcoholic fatty liver disease, nonalcoholic steatohepatitis and hepatic fibrosis, and focuses on the adverse effects of hyper O-GlcNAcylation on liver cancer progression and metabolic reprogramming.

Keywords:  O-GlcNAcylation; insulin signal; liver cancer; metabolism; nonalcoholic fatty liver disease

DOI:  https://doi.org/10.1111/liv.15812
MedComm (2020). 2023 Dec;4(6): e456

O-GlcNAcylation: cellular physiology and therapeutic target for human diseases.

Lin Ye, Wei Ding, Dandan Xiao, Yi Jia, Zhonghao Zhao, Xiang Ao, Jianxun Wang.

  O-linked-β-N-acetylglucosamine (O-GlcNAcylation) is a distinctive posttranslational protein modification involving the coordinated action of O-GlcNAc transferase and O-GlcNAcase, primarily targeting serine or threonine residues in various proteins. This modification impacts protein functionality, influencing stability, protein-protein interactions, and localization. Its interaction with other modifications such as phosphorylation and ubiquitination is becoming increasingly evident. Dysregulation of O-GlcNAcylation is associated with numerous human diseases, including diabetes, nervous system degeneration, and cancers. This review extensively explores the regulatory mechanisms of O-GlcNAcylation, its effects on cellular physiology, and its role in the pathogenesis of diseases. It examines the implications of aberrant O-GlcNAcylation in diabetes and tumorigenesis, highlighting novel insights into its potential role in cardiovascular diseases. The review also discusses the interplay of O-GlcNAcylation with other protein modifications and its impact on cell growth and metabolism. By synthesizing current research, this review elucidates the multifaceted roles of O-GlcNAcylation, providing a comprehensive reference for future studies. It underscores the potential of targeting the O-GlcNAcylation cycle in developing novel therapeutic strategies for various pathologies.

Keywords:  O‐GlcNAcylation; disease; pathological processes; protein functionality; protein posttranslational modifications; therapeutic strategies

DOI:  https://doi.org/10.1002/mco2.456
Endocr Metab Immune Disord Drug Targets. 2023 Dec 18.

Pre-implantation Genetic Testing in Inherited Metabolic Diseases? Stateof- the-art and current challenges.

Ana Miguel Capela, Ana Cunha, Ana Maria Fortuna, Cláudia Falcão Reis.

   INTRODUCTION: Inborn errors of metabolism (IEM) are genetic diseases involving congenital disorders of enzyme activities. Most follow Mendelian autosomal recessive inheritance and few follow mitochondrial inheritance. In many cases, after the birth of an affected child parents discover that have been the carriers for the condition and worry about the risk of recurrence in future offspring. Preimplantation genetic testing (PGT) can analyze embryos before their transfer to the uterus and prevent the transmission of hereditary conditions to descendants, however this procedure is of limited value in mtDNA conditions.
METHODS: The list of diseases currently approved for PGT were reviewed. The process for eligibility, was as for the Comissão Nacional Procriação Medicamente Assistida (CNPMA), of Portugal (PT). Review of international practices for Assisted Reproductive Techniques (ART) in IEM was carried out.
RESULTS: As of 07.2022, 23 IEM diseases associated with deleterious variants in nDNA were approved for PGT in PT. Couples at risk for conditions not included in the list can solicit an evaluation from an expert committee, after a medical genetics consultation. To qualify for approval, diseases must cause significant suffering and/or premature death. Due to a greater number of solicitations many more IEM conditions have been approved for PGT across the world. ART for mtDNA is not available in PT. International expert centers include PGT for specific well documented variants and mitochondrial donation.
CONCLUSION: PGT is a reliable approach to reduce the risk of transmission of a genetic condition to the offspring. The list of IEM disorders currently accepted for this technique in Portugal are small, but it is expanding, as many more diseases fit the necessary criteria. While appealing in theory, low success rates coupled with limited availability can be discouraging for patients. Genetic counselling is of paramount importance after the diagnosis of IEM diseases. It is important for both clinicians and patients to be made aware of the available reproductive options and their limitations.

Keywords:  Assisted Reproductive Techniques (ART); Genetic counselling; Inborn errors of metabolism (IEM); Preimplantation genetic testing (PGT); mtDNA

DOI:  https://doi.org/10.2174/0118715303279986231211090830
Sci Rep. 2023 Dec 20. 13(1): 22783

Untangling adaptive functioning of PMM2-CDG across age and its impact on parental stress: a cross-sectional study.

Florencia Epifani, Susana María Pujol Serra, Marta Llorens, Sol Balcells, Gregorio Nolasco, Mercè Bolasell, Sergio Aguilera-Albesa, Ramon Cancho Candela, José Luis Cuevas Cervera, Verónica García Sánchez, Oscar Garcia, María Concepción Miranda-Herrero, Pedro J Moreno-Lozano, Bernabé Robles, Susana Roldán Aparicio, Ramón Velázquez Fragua, Mercedes Serrano.

Phosphomannomutase deficiency (PMM2-CDG) leads to cerebellar atrophy with ataxia, dysmetria, and intellectual deficits. Despite advances in therapy, the cognitive and adaptive profile remains unknown. Our study explores the adaptive profile of 37 PMM2-CDG patients, examining its association with parental stress and medical characteristics. Assessment tools included ICARS for the cerebellar syndrome and NPCRS for global disease severity. Behavioral and adaptive evaluation consisted of the Vineland Adaptive Behavior Scale and the Health of the Nation Outcome Scales. Psychopathological screening involved the Child Behavior Checklist and the Symptom Check-List-90-R. Parental stress was evaluated using Parental Stress Index. Results were correlated with clinical features. No significant age or sex differences were found. 'Daily living skills' were notably affected. Patients severely affected exhibited lower adaptive skill values, as did those with lipodystrophy and inverted nipples. Greater severity in motor cerebellar syndrome, behavioral disturbances and the presence of comorbidities such as hyperactivity, autistic features and moderate-to-severe intellectual disability correlated with greater parental stress. Our study found no decline in adaptive abilities. We provide tools to assess adaptive deficits in PMM2-CDG patients, emphasizing the importance of addressing communication, daily living skills, and autonomy, and their impact on parental stress in clinical monitoring and future therapies.

DOI: https://doi.org/10.1038/s41598-023-49518-y
PeerJ. 2023 ;11 e16635

New insights into the role of GSK-3β in the brain: from neurodegenerative disease to tumorigenesis.

Shenjin Lai, Peng Wang, Jingru Gong, Shuaishuai Zhang.

  Glycogen synthase kinase 3 (GSK-3) is a serine/threonine kinase widely expressed in various tissues and organs. Unlike other kinases, GSK-3 is active under resting conditions and is inactivated upon stimulation. In mammals, GSK-3 includes GSK-3 α and GSK-3β isoforms encoded by two homologous genes, namely, GSK3A and GSK3B. GSK-3β is essential for the control of glucose metabolism, signal transduction, and tissue homeostasis. As more than 100 known proteins have been identified as GSK-3β substrates, it is sometimes referred to as a moonlighting kinase. Previous studies have elucidated the regulation modes of GSK-3β. GSK-3β is involved in almost all aspects of brain functions, such as neuronal morphology, synapse formation, neuroinflammation, and neurological disorders. Recently, several comparatively specific small molecules have facilitated the chemical manipulation of this enzyme within cellular systems, leading to the discovery of novel inhibitors for GSK-3β. Despite these advancements, the therapeutic significance of GSK-3β as a drug target is still complicated by uncertainties surrounding the potential of inhibitors to stimulate tumorigenesis. This review provides a comprehensive overview of the intricate mechanisms of this enzyme and evaluates the existing evidence regarding the therapeutic potential of GSK-3β in brain diseases, including Alzheimer's disease, Parkinson's disease, mood disorders, and glioblastoma.

Keywords:  Alzheimer’s disease; GSK-3β; Glioblastoma; Neuroinflammation; Parkinson’s disease; Synaptic plasticity

DOI:  https://doi.org/10.7717/peerj.16635