bims-glecem 2022-10-09 papers

Issue of 2022‒10‒09
six papers selected by
Dipsikha Biswas, Københavns Universitet

Nat Commun. 2022 Oct 03. 13(1): 5834

Allosteric regulation of glycogen breakdown by the second messenger cyclic di-GMP.

Maria A Schumacher, Mirka E Wörmann, Max Henderson, Raul Salinas, Andreas Latoscha, Mahmoud M Al-Bassam, Kumar Siddharth Singh, Elaine Barclay, Katrin Gunka, Natalia Tschowri.

Streptomyces are our principal source of antibiotics, which they generate concomitant with a complex developmental transition from vegetative hyphae to spores. c-di-GMP acts as a linchpin in this transition by binding and regulating the key developmental regulators, BldD and WhiG. Here we show that c-di-GMP also binds the glycogen-debranching-enzyme, GlgX, uncovering a direct link between c-di-GMP and glycogen metabolism in bacteria. Further, we show c-di-GMP binding is required for GlgX activity. We describe structures of apo and c-di-GMP-bound GlgX and, strikingly, their comparison shows c-di-GMP induces long-range conformational changes, reorganizing the catalytic pocket to an active state. Glycogen is an important glucose storage compound that enables animals to cope with starvation and stress. Our in vivo studies reveal the important biological role of GlgX in Streptomyces glucose availability control. Overall, we identify a function of c-di-GMP in controlling energy storage metabolism in bacteria, which is widespread in Actinobacteria.

DOI: https://doi.org/10.1038/s41467-022-33537-w

Int J Biol Macromol. 2022 Sep 29. pii: S0141-8130(22)02172-9. [Epub ahead of print]222(Pt A): 1027-1036

Rapid discrimination of glycogen particles originated from different eukaryotic organisms.

Jia-Wei Tang, Rui Qiao, Xue-Song Xiong, Bing-Xin Tang, You-Wei He, Ying-Ying Yang, Pei Ju, Peng-Bo Wen, Xiao Zhang, Liang Wang.

There are many commercially available glycogen particles in the market due to their bioactive functions as food additive, drug carrier and natural moisturizer, etc. It would be beneficial to rapidly determine the origins of commercially-available glycogen particles, which could facilitate the establishment of quality control methodology for glycogen-containing products. With its non-destructive, label-free and low-cost features, surface enhanced Raman spectroscopy (SERS) is an attractive technique with high potential to discriminate chemical compounds in a rapid mode. In this study, we applied the combination of SERS technique and machine leaning algorithms on glycogen analysis, which successfully predicted the origins of glycogen particles from a variety of organisms with convolutional neural network (CNN) algorithm plus attention mechanism having the best computational performance (5-fold cross validation accuracy = 96.97 %). In sum, this is the first study focusing on the discrimination of commercial glycogen particles originated from different organisms, which holds the application potential in quality control of glycogen-containing products.

Keywords: Glycogen; Machine learning algorithm; SERS

DOI: https://doi.org/10.1016/j.ijbiomac.2022.09.233

Front Cardiovasc Med. 2022 ;9 899283

De novo LAMP2 insertion mutation causes cardiac-only Danon disease: A case report.

James Jiqi Wang, Bo Yu, Xiuli Song, Hong Wang.

Danon disease is a rare disease caused by glycogen storage lysosomal disorder. It is related to the pathogenic mutation of the LAMP2 gene. In this case report, we present a patient with a novel pathogenic mutation (c.764_765insGA) with cardiac-only symptoms. Her family members do not carry the same mutation she does, suggesting this is a de novo mutation. Further tests revealed vacuoles and glycogen disposition in the patient's heart tissue and a significant decrease in LAMP2 protein expression. Protein structure remodeling of LAMP2 predicted that the mutant protein has conformational change lacking an important transmembrane domain, subsequently causing protein destabilization.

Keywords: Danon disease; LAMP2; Sanger sequencing; genetic diagnosis; hypertrophy

DOI: https://doi.org/10.3389/fcvm.2022.899283

Mol Metab. 2022 Oct 02. pii: S2212-8778(22)00178-8. [Epub ahead of print] 101609

Hepatic glycerol shunt and glycerol-3-phosphate phosphatase control liver metabolism and glucodetoxification under hyperglycemia.

Anfal Al-Mass, Pegah Poursharifi, Marie-Line Peyot, Roxane Lussier, Isabelle Chenier, Yat Hei Leung, Anindya Ghosh, Abel Oppong, Elite Possik, Yves Mugabo, Rasheed Ahmad, Robert Sladek, S R Murthy Madiraju, Fahd Al-Mulla, Marc Prentki.

OBJECTIVE: Glycerol-3-phosphate (Gro3P) phosphatase (G3PP) hydrolyzes Gro3P to glycerol that exits the cell, thereby operating a "glycerol shunt", a metabolic pathway that we identified recently in mammalian cells. We have investigated the role of G3PP and the glycerol shunt in the regulation of glucose metabolism and lipogenesis in mouse liver.METHODS: We generated hepatocyte-specific G3PP-KO mice (LKO), by injecting AAV8-TBG-iCre to male G3PPfl/fl mice. Controls received AAV8-TBG-eGFP. Both groups were fed chow diet for 10 weeks. Hyperglycemia (16-20 mM) was induced by glucose infusion for 55 h. Hepatocytes were isolated from normoglycemic mice for ex vivo studies and targeted metabolomics were measured in mice liver after glucose infusion.
RESULTS: LKO mice showed no change in body weight, food intake, fed and fasted glycemia but had increased fed plasma triglycerides. Hepatic glucose production from glycerol was increased in fasted LKO mice. LKO mouse hepatocytes displayed reduced glycerol production, elevated triglyceride and lactate production at high glucose concentration. Hyperglycemia in LKO mice led to increased liver weight and accumulation of triglycerides, glycogen and cholesterol together with elevated levels of Gro3P, dihydroxyacetone phosphate, acetyl-CoA and some Krebs cycle intermediates in liver. Hyperglycemic LKO mouse liver showed elevated expression of proinflammatory cytokines and M1-macrophage markers accompanied by increased plasma triglycerides, LDL/VLDL, urea and uric acid and myocardial triglycerides.
CONCLUSIONS: The glycerol shunt orchestrated by G3PP acts as a glucose excess detoxification pathway in hepatocytes by preventing metabolic disturbances that contribute to enhanced liver fat, glycogen storage, inflammation and lipid build-up in the heart. We propose G3PP as a novel therapeutic target for hepatic disorders linked to nutrient excess.

Keywords: Glucodetoxification; Glycerol shunt; Glycerol-3-phosphate phosphatase; Hepatocytes; Liver; NAFLD; cholesterol; glycogen; inflammation; lipogenesis; triglycerides

DOI: https://doi.org/10.1016/j.molmet.2022.101609

Biol Pharm Bull. 2022 ;45(10): 1525-1530

Inhibition of Glycogen Synthase Kinase 3ß Enhances Functions of Induced Pluripotent Stem Cell-Derived Brain Microvascular Endothelial Cells in the Blood-Brain Barrier.

Tomoko Yamaguchi, Misae Nishijima, Kenji Kawabata.

Brain microvascular endothelial cells (BMECs) are essential component of the blood-brain barrier (BBB). BMECs strictly regulate the entry of various molecules into the central nervous system from the peripheral circulation by forming tight junctions and expressing various influx/efflux transporters and receptors. In vitro BBB models have been widely reported with primary BMECs isolated from animals, although it is known that the expression patterns and levels of transporters and receptors in BMECs differ between humans and animals. Recently, several methods to differentiate BMECs from human induced pluripotent stem (hiPS) cell have been developed. However, the expression of P-glycoprotein (P-gp), which is a key efflux transporter, in hiPS cell-derived BMECs was detected at a relatively low level compared with primary human BMECs. In this study, we examined the involvement of the canonical Wnt signaling pathway, which contributes to the development of BBB formation, in the regulation of P-gp expression in hiPS cell-derived BMECs. We found that the barrier integrity was significantly enhanced in hiPS cell-derived BMECs treated with glycogen synthase kinase-3ß (GSK-3ß) inhibitors, which are known to positively regulate the canonical Wnt signaling pathway. In addition, our data also showed P-gp expression level was increased by treatment with GSK-3ß inhibitors. In conclusion, physiological barrier function and P-gp expression in BMECs can be enhanced by the canonical Wnt signaling pathway. Our results may be useful for promoting the development of drugs for central nervous system diseases using in vitro BBB model.

Keywords: P-glycooprotein; Wnt signaling; blood–brain barrier; induced pluripotent stem (iPS) cell

DOI: https://doi.org/10.1248/bpb.b22-00393

J Med Case Rep. 2022 Oct 03. 16(1): 360

Lafora disease: a case report.

Naim Zeka, Leonore Zogaj, Abdurrahim Gerguri, Ramush Bejiqi, Ragip Ratkoceri, Arlinda Maloku, Aferdita Mustafa, Labinot Shahini, Jeton Maxharaj.

BACKGROUND: Lafora disease is a rare genetic disorder involving glycogen metabolism disorder. It is inherited by autosomal recessive pattern presenting as a progressive myoclonus epilepsy and neurologic deterioration beginning in adolescence. It is characterized by Lafora bodies in tissues such as brain, skin, muscle, and liver.CASE PRESENTATION: We report a rare case of Lafora disease in a 16-year-old Albanian girl who presented at a tertiary health care center with generalized tonic-clonic seizures, eyelid twitches, hallucinations, headache, and cognitive dysfunction. She was initially treated for generalized epilepsy and received an antiepileptic drug. However, owing to resistance of seizures to this antiepileptic drug, a second drug was introduced. However, seizures continued despite compliance with therapy, and general neurological status began to deteriorate. The child began to have hallucinations and decline of cognitive function. She developed dysarthria and unsteady gait. When admitted to the hospital, blood tests and imaging examinations were planned. The blood tests were unremarkable. There was no relevant family history and no consanguinity. Electroencephalography showed multifocal discharges in both hemispheres, and brain magnetic resonance imaging revealed no abnormality. Axillary skin biopsy revealed inclusion bodies in apocrine glands. Consequently, the child was referred to an advanced center for genetic testing, which also confirmed diagnosis of Lafora disease with a positive mutation on NHLRC1 gene.
CONCLUSIONS: Even though rare as a condition, Lafora disease should be considered on differential diagnosis in progressive and drug-refractory epilepsy in adolescents, especially when followed by cognitive decline.

Keywords: Epilepsy; Inclusion bodies; Lafora disease

DOI: https://doi.org/10.1186/s13256-022-03537-x