bims-glecem 2022-08-14 papers

Issue of 2022‒08‒14
seven papers selected by
Dipsikha Biswas, Københavns Universitet

Neuromuscul Disord. 2022 Jul 13. pii: S0960-8966(22)00599-5. [Epub ahead of print]

Glycogen accumulation in GNE myopathy.

Andre Granger, Marcus V Pinto, Margherita Milone, Teerin Liewluck.

Keywords: Distal myopathy; GNE myopathy; Glycogen; Rimmed vacuoles

DOI: https://doi.org/10.1016/j.nmd.2022.07.396

CNS Neurosci Ther. 2022 Aug 11.

Novel PHKA1 mutation in glycogen storage disease type IXD with typical myotonic discharges.

Cong-Cong Wang, Bing Yang, Ying Liu, Xiao-Li Li, Bin Liu, Rui-Sheng Duan.

Keywords: PHKA1; glycogen storage disease type IXD; novel mutation; typical myotonic discharges

DOI: https://doi.org/10.1111/cns.13939

Curr Opin Pediatr. 2022 Aug 04.

Update on glycogen storage disease: primary hepatic involvement.

Tiffany L Freeney Wright, Luis A Umaña, Charina M Ramirez.

PURPOSE OF REVIEW: Glycogen storage disease is a group of disorders primarily characterized by hepatomegaly and fasting hypoglycemia. This group of disorders may also affect the muscle, kidneys, and neurodevelopment. With an overall prevalence of 1 : 20 000, GSDs are disorders that clinicians should diagnose in a timely manner because adequate management can prevent complications, such as neurodevelopmental delay and liver disease [1]. As there are numerous types of GSDs, being able to distinguish one type from another can be overwhelming. In this review, we focus on hepatic GSDs to provide a concise review of clinical presentation, diagnosis, and current management.RECENT FINDINGS: GSDs are considered rare disorders, and one of the main challenges is the delay in diagnosis, misdiagnosis, or under diagnosis. However, with molecular genetic testing now readily available, confirming the diagnosis is no longer as difficult or invasive as it was in the past.
SUMMARY: Current therapy for this group of disorders requires maintaining stable glucose levels. Avoiding hypoglycemia, as well as hyperglycemia, is critical in managing these patients. Being able to distinguish the types of GSDs and understanding the specific treatments for each enzymatic defect will optimize patient care.

DOI: https://doi.org/10.1097/MOP.0000000000001158

Hum Mol Genet. 2022 Aug 12. pii: ddac197. [Epub ahead of print]

Molecular mechanism underlying impaired hepatic autophagy in glycogen storage disease type Ib.

Sudeep Gautam, Lisa Zhang, Cheol Lee, Irina Arnaoutova, Hung Dar Chen, Roberta Resaz, Alessandra Eva, Brian C Mansfield, Janice Y Chou.

Type Ib glycogen storage disease (GSD-Ib) is caused by a deficiency in the G6P transporter (G6PT) that translocates G6P from the cytoplasm into the endoplasmic reticulum lumen, where the intraluminal G6P is hydrolyzed to glucose by glucose-6-phosphatase-α (G6Pase-α). Clinically, GSD-Ib patients manifest a metabolic phenotype of impaired blood glucose homeostasis and a long-term risk of hepatocellular adenoma/carcinoma (HCA/HCC). Studies have shown that autophagy deficiency contributes to hepatocarcinogenesis. In this study, we show that G6PT deficiency leads to impaired hepatic autophagy evident from attenuated expression of many components of the autophagy network, decreased autophagosome formation, and reduced autophagy flux. The G6PT-deficient liver displayed impaired SIRT1 and AMP-activated protein kinase (AMPK) signaling, along with reduced expression of SIRT1, forkhead boxO3a (FoxO3a), liver kinase B-1 (LKB1), and the active p-AMPK. Importantly, we show that overexpression of either SIRT1 or LKB1 in G6PT-deficient liver restored autophagy and SIRT1/FoxO3a and LKB1/AMPK signaling. The hepatosteatosis in G6PT-deficient liver decreased SIRT1 expression. LKB1 overexpression reduced hepatic triglycerides levels, providing a potential link between LKB1/AMPK signaling upregulation and the increase in SIRT1 expression. In conclusion, downregulation of SIRT1/FoxO3a and LKB1/AMPK signaling underlies impaired hepatic autophagy which may contribute to HCA/HCC development in GSD-Ib. Understanding this mechanism may guide future therapies.

DOI: https://doi.org/10.1093/hmg/ddac197

Neurotox Res. 2022 Aug 11.

Inhibition of NLRP1-Dependent Pyroptosis Prevents Glycogen Synthase Kinase-3β Overactivation-Induced Hyperphosphorylated Tau in Rats.

Xiangying Liu, Wenjing Song, Ying Yu, Jianhua Su, Xiaoyan Shi, Xin Yang, Honghui Wang, Peng Liu, Libo Zou.

Our previous study indicated that inhibition of NLRP1-dependent pyroptosis could decrease intracerebroventricular (ICV) injection of a protein kinase A (PKA) agonist- or streptozotocin (STZ)-induced hyperphosphorylated tau. In this study, we used a glycogen synthase kinase-3β (GSK-3β) overactivation rat model to reconfirm our previous results. ICV injection of wortmannin (WT, a PI3K inhibitor) and GF-109203X (GFX, a PKC inhibitor) was used to induce overactivation of GSK-3β in rats. We injected NLRP1 siRNA together with WT/GFX to evaluate the effect of the inhibition of NLRP1-dependent neuronal pyroptosis on hyperphosphorylated tau. Our results indicated that ICV injection of NLRP1 siRNA prevented ICV-WT/GFX-induced neuronal death, further improving the spatial memory of the rats in the Morris water maze test. ICV injection of NLRP1 siRNA downregulated the expression of ASC, caspase-1, and GSDMD and the contents of IL-1β and IL-18 in rat brains. ICV injection of NLRP1 siRNA also decreased hyperphosphorylated tau and the activity of GSK-3β. Thus, these results support our previous study that NLRP1-dependent pyroptosis could enhance hyperphosphorylation of tau protein.

Keywords: GSK3β; Hyperphosphorylated tau; NLRP1; Pyroptosis

DOI: https://doi.org/10.1007/s12640-022-00554-y

Spectrochim Acta A Mol Biomol Spectrosc. 2022 Jul 03. pii: S1386-1425(22)00733-8. [Epub ahead of print]281 121584

Spectrofluorometric method for detection glycogen using chemically gold nanoparticles: Cyanobacteria as biological model.

Esam M Bakir, Nermin A El Semary.

There is a need for simple spectrofluorimetric method for detection of glycogen molecule based on binding to nanogold. Here we propose such a quantification method for glycogen using cyanobacteria as a biological model. Biologically, two strains of cyanobacteria were selected based on their previously tested nanogold biosynthetic abilities. Chemically, spherical gold nanoparticles were prepared and tested for binding to the glycogen molecule. Experimental analyses were conducted to determine the morphological and optical properties of the Au-glycogen hydrocolloids. Results: The plasmon band of biosynthesized AuNPs-glycogen was centered at 520-540 nm with size diameter was 41.7 ± 0.2 nm. The vibrational bands of glycogen were observed at 1,000 to 1,200 cm-1. The Au3+/Au0 redox coupling cycle was observed. The luminescence of AuNPs showed more stability by the addition of gradual concentrations of glycogen molecules. The detection (LOD) and quantitation limits (LOQ) were observed to be 0.89 and 2.95 µmol L-1 respectively (R2 = 0.99). The good chemical stability of this colloidal system and the glycogen molecule studied via density functional theory (DFT). The HOMO level of glycogen unit was closed near to LUMO level of Au3+. Conclusion: The associations formed between the gold nanoparticles and glycogen resulted in good chemical stability. This indicates that the quantification method proposed can be stably applied.

Keywords: Au-glycogen 3; Cyanobacteria model4 HOMO and LUMO energy5; Gold nanoparticles 2; Spectrofluorometric1

DOI: https://doi.org/10.1016/j.saa.2022.121584

J Biol Chem. 2022 Aug 09. pii: S0021-9258(22)00803-1. [Epub ahead of print] 102360

Functional inactivation of Plasmodium falciparum glycogen synthase kinase GSK3 modulates erythrocyte invasion and blocks gametocyte maturation.

Arne Alder, Louisa Wilcke, Emma Pietsch, Heidrun von Thien, Samuel Pazicky, Christian Löw, Paolo Mesen-Ramirez, Anna Bachmann, Paul-Christian Burda, Conrad Kunick, Holger Sondermann, Danny Wilson, Tim-Wolf Gilberger.

Malaria is responsible for hundreds of thousands of deaths every year. The lack of an effective vaccine and the global spread of multi-drug resistant parasites hampers the fight against the disease and underlines the need for new antimalarial drugs. Central to the pathogenesis of malaria is the proliferation of Plasmodium parasites within human erythrocytes. Parasites invade erythrocytes via a coordinated sequence of receptor-ligand interactions between the parasite and the host cell. Post-translational modifications such as protein phosphorylation are known to be key regulators in this process and are mediated by protein kinases. For several parasite kinases, including the Plasmodium falciparum Glycogen Synthase Kinase 3 (PfGSK3), inhibitors have been shown to block erythrocyte invasion. Here, we provide an assessment of PfGSK3 function by reverse genetics. Using targeted gene disruption, we show the active gene copy, PfGSK3β, is not essential for asexual blood stage proliferation, although it modulates efficient erythrocyte invasion. We found functional inactivation leads to a 69% decreased growth rate and confirmed this growth defect by rescue experiments with wild-type and catalytically inactive mutants. Functional knock-out of PfGSK3β does not lead to transcriptional up-regulation of the second copy of PfGSK3. We further analyze expression, localization, and function of PfGSK3β during gametocytogenesis using a parasite line allowing conditional induction of sexual commitment. We demonstrate PfGSK3β-deficient gametocytes show a strikingly malformed morphology leading to the death of parasites in later stages of gametocyte development. Taken together, these findings are important for our understanding and the development of PfGSK3 as an anti-malarial target.

Keywords: GSK3; Gametocytogenesis; Host Cell Invasion; Kinase; Malaria; Plasmodium falciparum

DOI: https://doi.org/10.1016/j.jbc.2022.102360