bims-meglyc 2024-03-17 papers

Issue of 2024–03–17
five papers selected by
Silvia Radenkovic, UMC Utrecht

Proteomics. 2024 Mar 12. e2400012

Dysregulated proteome and N-glycoproteome in ALG1-deficient fibroblasts.

Rohit Budhraja, Neha Joshi, Silvia Radenkovic, Tamas Kozicz, Eva Morava, Akhilesh Pandey.

Asparagine-linked glycosylation 1 protein is a β-1,4-mannosyltransferase, is encoded by the ALG1 gene, which catalyzes the first step of mannosylation in N-glycosylation. Pathogenic variants in ALG1 cause a rare autosomal recessive disorder termed as ALG1-CDG. We performed a quantitative proteomics and N-glycoproteomics study in fibroblasts derived from patients with one homozygous and two compound heterozygous pathogenic variants in ALG1. Several proteins that exhibited significant upregulation included insulin-like growth factor II and pleckstrin, whereas hyaluronan and proteoglycan link protein 1 was downregulated. These proteins are crucial for cell growth, survival and differentiation. Additionally, we observed a decrease in the expression of mitochondrial proteins and an increase in autophagy-related proteins, suggesting mitochondrial and cellular stress. N-glycoproteomics revealed the reduction in high-mannose and complex/hybrid glycopeptides derived from numerous proteins in patients explaining that defect in ALG1 has broad effects on glycosylation. Further, we detected an increase in several short oligosaccharides, including chitobiose (HexNAc2 ) trisaccharides (Hex-HexNAc2 ) and novel tetrasaccharides (NeuAc-Hex-HexNAc2 ) derived from essential proteins including LAMP1, CD44 and integrin. These changes in glycosylation were observed in all patients irrespective of their gene variants. Overall, our findings not only provide novel molecular insights into understanding ALG1-CDG but also offer short oligosaccharide-bearing peptides as potential biomarkers.

Keywords: ALG1-CDG; LC-MS/MS; biomarker; congenital disorders of glycosylation; glycoproteomics; proteomics

DOI: https://doi.org/10.1002/pmic.202400012

Front Physiol. 2024 ;15 1360891

Uridine and its role in metabolic diseases, tumors, and neurodegenerative diseases.

Yueyuan Yang, Yahong Ye, Yingfeng Deng, Ling Gao.

Uridine is a pyrimidine nucleoside found in plasma and cerebrospinal fluid with a concentration higher than the other nucleosides. As a simple metabolite, uridine plays a pivotal role in various biological processes. In addition to nucleic acid synthesis, uridine is critical to glycogen synthesis through the formation of uridine diphosphate glucose in which promotes the production of UDP-GlcNAc in the hexosamine biosynthetic pathway and supplies UDP-GlcNAc for O-GlcNAcylation. This process can regulate protein modification and affect its function. Moreover, Uridine has an effect on body temperature and circadian rhythms, which can regulate the metabolic rate and the expression of metabolic genes. Abnormal levels of blood uridine have been found in people with diabetes and obesity, suggesting a link of uridine dysregulation and metabolic disorders. At present, the role of uridine in glucose metabolism and lipid metabolism is controversial, and the mechanism is not clear, but it shows the trend of long-term damage and short-term benefit. Therefore, maintaining uridine homeostasis is essential for maintaining basic functions and normal metabolism. This article summarizes the latest findings about the metabolic effects of uridine and the potential of uridine metabolism as therapeutic target in treatment of metabolic disorders.

Keywords: O-GlcNAc; circadian rhythm; diabetes; metabolic diseases; neurodegenerative diseases; obesity; uridine

DOI: https://doi.org/10.3389/fphys.2024.1360891

Drug Saf. 2024 Mar 14.

The Role of Pharmacogenomics in Rare Diseases.

Alice Man, Gabriella S S Groeneweg, Colin J D Ross, Bruce C Carleton.

Rare diseases have become an increasingly important public health priority due to their collective prevalence and often life-threatening nature. Incentive programs, such as the Orphan Drug Act have been introduced to increase the development of rare disease therapeutics. While the approval of these therapeutics requires supportive data from stringent pre-market studies, these data lack the ability to describe the causes of treatment response heterogeneity, leading to medications often being more harmful or less effective than predicted. If a Goal Line were to be used to describe the multifactorial continuum of phenotypic variations occurring in response to a medication, the 'Goal Posts', or the two defining points of this continuum, would be (1) Super-Response, or an extraordinary therapeutic effect; and (2) Serious Harm. Investigation of the pharmacogenomics behind these two extreme phenotypes can potentially lead to the development of new therapeutics, help inform rational use criteria in drug policy, and improve the understanding of underlying disease pathophysiology. In the context of rare diseases where cohort sizes are smaller than ideal, 'small data' and 'big data' approaches to data collection and analysis should be combined to produce the most robust results. This paper presents the importance of studying drug response in parallel to other research initiatives in rare diseases, as well as the need for international collaboration in the area of rare disease pharmacogenomics.

DOI: https://doi.org/10.1007/s40264-024-01416-6

Neurosci Bull. 2024 Mar 11.

Emerging Human Pluripotent Stem Cell-Based Human-Animal Brain Chimeras for Advancing Disease Modeling and Cell Therapy for Neurological Disorders.

Yanru Ji, Jenna Lillie McLean, Ranjie Xu.

Human pluripotent stem cell (hPSC) models provide unprecedented opportunities to study human neurological disorders by recapitulating human-specific disease mechanisms. In particular, hPSC-based human-animal brain chimeras enable the study of human cell pathophysiology in vivo. In chimeric brains, human neural and immune cells can maintain human-specific features, undergo maturation, and functionally integrate into host brains, allowing scientists to study how human cells impact neural circuits and animal behaviors. The emerging human-animal brain chimeras hold promise for modeling human brain cells and their interactions in health and disease, elucidating the disease mechanism from molecular and cellular to circuit and behavioral levels, and testing the efficacy of cell therapy interventions. Here, we discuss recent advances in the generation and applications of using human-animal chimeric brain models for the study of neurological disorders, including disease modeling and cell therapy.

Keywords: Cell therapy; Disease modeling; Human neurons and glia; Human pluripotent stem cell; Human–animal chimera; Microglia; Neurological disorder; Organoid

DOI: https://doi.org/10.1007/s12264-024-01189-z

Curr Heart Fail Rep. 2024 Mar 15.

Non-Coding Ribonucleic Acids as Diagnostic and Therapeutic Targets in Cardiac Fibrosis.

Samuel R Olson, W H Wilson Tang, Chia-Feng Liu.

PURPOSE OF REVIEW: Cardiac fibrosis is a crucial juncture following cardiac injury and a precursor for many clinical heart disease manifestations. Epigenetic modulators, particularly non-coding RNAs (ncRNAs), are gaining prominence as diagnostic and therapeutic tools.
RECENT FINDINGS: miRNAs are short linear RNA molecules involved in post-transcriptional regulation; lncRNAs and circRNAs are RNA sequences greater than 200 nucleotides that also play roles in regulating gene expression through a variety of mechanisms including miRNA sponging, direct interaction with mRNA, providing protein scaffolding, and encoding their own products. NcRNAs have the capacity to regulate one another and form sophisticated regulatory networks. The individual roles and disease relevance of miRNAs, lncRNAs, and circRNAs to cardiac fibrosis have been increasingly well described, though the complexity of their interrelationships, regulatory dynamics, and context-specific roles needs further elucidation. This review provides an overview of select ncRNAs relevant in cardiac fibrosis as a surrogate for many cardiac disease states with a focus on crosstalk and regulatory networks, variable actions among different disease states, and the clinical implications thereof. Further, the clinical feasibility of diagnostic and therapeutic applications as well as the strategies underway to advance ncRNA theranostics is explored.

Keywords: Cardiac fibrosis; Circular RNA (circRNA); Epigenetic modulation; Long non-coding RNA (lncRNA); Non-coding RNAs; Regulatory networks; microRNA (miRNA)

DOI: https://doi.org/10.1007/s11897-024-00653-1