bims-meglyc 2023-06-04 papers

Cell Rep Med. 2023 May 23. pii: S2666-3791(23)00170-2. [Epub ahead of print] 101056

Tracer metabolomics reveals the role of aldose reductase in glycosylation.

Abnormal polyol metabolism is predominantly associated with diabetes, where excess glucose is converted to sorbitol by aldose reductase (AR). Recently, abnormal polyol metabolism has been implicated in phosphomannomutase 2 congenital disorder of glycosylation (PMM2-CDG) and an AR inhibitor, epalrestat, proposed as a potential therapy. Considering that the PMM2 enzyme is not directly involved in polyol metabolism, the increased polyol production and epalrestat's therapeutic mechanism in PMM2-CDG remained elusive. PMM2-CDG, caused by PMM2 deficiency, presents with depleted GDP-mannose and abnormal glycosylation. Here, we show that, apart from glycosylation abnormalities, PMM2 deficiency affects intracellular glucose flux, resulting in polyol increase. Targeting AR with epalrestat decreases polyols and increases GDP-mannose both in patient-derived fibroblasts and in pmm2 mutant zebrafish. Using tracer studies, we demonstrate that AR inhibition diverts glucose flux away from polyol production toward the synthesis of sugar nucleotides, and ultimately glycosylation. Finally, PMM2-CDG individuals treated with epalrestat show a clinical and biochemical improvement.

Keywords: aldose reductase; aldose reductase inhibition; congenital disorder of glycosylation; glycosylation; phoshomannomutase-2 deficiency; polyol metabolism

DOI: https://doi.org/10.1016/j.xcrm.2023.101056

Mol Genet Metab. 2023 May 16. pii: S1096-7192(23)00240-8. [Epub ahead of print]139(3): 107610

Complex metabolic disharmony in PMM2-CDG paves the way to new therapeutic approaches.

Nastassja Himmelreich, Frauke Kikul, Lucie Zdrazilova, Tomáš Honzik, Andreas Hecker, Gernot Poschet, Christian Lüchtenborg, Britta Brügger, Sabine Strahl, Friederike Bürger, Jürgen G Okun, Hana Hansikova, Christian Thiel.

PMM2-CDG is the most common defect among the congenital disorders of glycosylation. In order to investigate the effect of hypoglycosylation on important cellular pathways, we performed extensive biochemical studies on skin fibroblasts of PMM2-CDG patients. Among others, acylcarnitines, amino acids, lysosomal proteins, organic acids and lipids were measured, which all revealed significant abnormalities. There was an increased expression of acylcarnitines and amino acids associated with increased amounts of calnexin, calreticulin and protein-disulfid-isomerase in combination with intensified amounts of ubiquitinylated proteins. Lysosomal enzyme activities were widely decreased as well as citrate and pyruvate levels indicating mitochondrial dysfunction. Main lipid classes such as phosphatidylethanolamine, cholesterol or alkyl-phosphatidylcholine, as well as minor lipid species like hexosylceramide, lysophosphatidylcholines or phosphatidylglycerol, were abnormal. Biotinidase and catalase activities were severely reduced. In this study we discuss the impact of metabolite abnormalities on the phenotype of PMM2-CDG. In addition, based on our data we propose new and easy-to-implement therapeutic approaches for PMM2-CDG patients.

Keywords: CDG-Ia; Congenital disorders of glycosylation; Fibroblasts; OMICS; PMM2-CDG; Therapeutic ideas

DOI: https://doi.org/10.1016/j.ymgme.2023.107610

Cells Dev. 2023 May 29. pii: S2667-2901(23)00033-5. [Epub ahead of print] 203857

Human pluripotent stem cell-based models of heart development and disease.

Gabriel Velichkova, Gergana Dobreva.

The heart is a complex organ composed of distinct cell types, such as cardiomyocytes, cardiac fibroblasts, endothelial cells, smooth muscle cells, neuronal cells and immune cells. All these cell types contribute to the structural, electrical and mechanical properties of the heart. Genetic manipulation and lineage tracing studies in mice have been instrumental in gaining critical insights into the networks regulating cardiac cell lineage specification, cell fate and plasticity. Such knowledge has been of fundamental importance for the development of efficient protocols for the directed differentiation of pluripotent stem cells (PSCs) in highly specialized cardiac cell types. In this review, we summarize the evolution and current advances in protocols for cardiac subtype specification, maturation, and assembly in cardiac microtissues and organoids.

Keywords: Cardiac differentiation; Cardiac organoids; Cardiovascular cell fate; ESCs; Heart-on-a-chip; hPSCs; iPSCs

DOI: https://doi.org/10.1016/j.cdev.2023.203857

Nat Methods. 2023 May 29.

Machine learning in rare disease.

Jineta Banerjee, Jaclyn N Taroni, Robert J Allaway, Deepashree Venkatesh Prasad, Justin Guinney, Casey Greene.

High-throughput profiling methods (such as genomics or imaging) have accelerated basic research and made deep molecular characterization of patient samples routine. These approaches provide a rich portrait of genes, molecular pathways and cell types involved in disease phenotypes. Machine learning (ML) can be a useful tool for extracting disease-relevant patterns from high-dimensional datasets. However, depending upon the complexity of the biological question, machine learning often requires many samples to identify recurrent and biologically meaningful patterns. Rare diseases are inherently limited in clinical cases, leading to few samples to study. In this Perspective, we outline the challenges and emerging solutions for using ML for small sample sets, specifically in rare diseases. Advances in ML methods for rare diseases are likely to be informative for applications beyond rare diseases for which few samples exist with high-dimensional data. We propose that the method community prioritize the development of ML techniques for rare disease research.

DOI: https://doi.org/10.1038/s41592-023-01886-z