Further Characterization of Glycogen from Type‐IV Glycogen‐Storage Disease

Mercier, Christiane; Whelan, W. J.

doi:10.1111/j.1432-1033.1973.tb03189.x

Cited by 12 publications

(4 citation statements)

References 5 publications

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“…8 GBE1 deficiency results in an imbalance between chain branching and elongation, and the formation of poorly branched glycogen. 9 The overly long chains of the poorly branched molecules wind round each other and extrude water, 10 leading the molecules to precipitate and aggregate into pathogenic inclusions called polyglucosan bodies (PBs). Being out of solution, PBs cannot be metabolized and accumulate with age, in most tissues eventually exceeding the amount of soluble glycogen.…”

Section: Introductionmentioning

confidence: 99%

“…GBE1 is responsible for catalyzing regular branch points in glycogen molecules and acts in concert with glycogen synthase (GYS), responsible for linear glycogen chain elongation, to form highly branched, soluble glycogen molecules 8 . GBE1 deficiency results in an imbalance between chain branching and elongation, and the formation of poorly branched glycogen 9 . The overly long chains of the poorly branched molecules wind round each other and extrude water, 10 leading the molecules to precipitate and aggregate into pathogenic inclusions called polyglucosan bodies (PBs).…”

Section: Introductionmentioning

confidence: 99%

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GYS1 or PPP1R3C deficiency rescues murine adult polyglucosan body disease

Chown

Wang

Zhao

et al. 2020

Ann Clin Transl Neurol

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Objective: Adult polyglucosan body disease (APBD) is an adult-onset neurological variant of glycogen storage disease type IV. APBD is caused by recessive mutations in the glycogen branching enzyme gene, and the consequent accumulation of poorly branched glycogen aggregates called polyglucosan bodies in the nervous system. There are presently no treatments for APBD. Here, we test whether downregulation of glycogen synthesis is therapeutic in a mouse model of the disease. Methods: We characterized the effects of knocking out two proglycogenic proteins in an APBD mouse model. APBD mice were crossed with mice deficient in glycogen synthase (GYS1), or mice deficient in protein phosphatase 1 regulatory subunit 3C (PPP1R3C), a protein involved in the activation of GYS1. Phenotypic and histological parameters were analyzed and glycogen was quantified. Results: APBD mice deficient in GYS1 or PPP1R3C demonstrated improvements in life span, morphology, and behavioral assays of neuromuscular function. Histological analysis revealed a reduction in polyglucosan body accumulation and of astro-and micro-gliosis in the brains of GYS1-and PPP1R3C-deficient APBD mice. Brain glycogen quantification confirmed the reduction in abnormal glycogen accumulation. Analysis of skeletal muscle, heart, and liver found that GYS1 deficiency reduced polyglucosan body accumulation in all three tissues and PPP1R3C knockout reduced skeletal muscle polyglucosan bodies. Interpretation: GYS1 and PPP1R3C are effective therapeutic targets in the APBD mouse model. These findings represent a critical step toward the development of a treatment for APBD and potentially other glycogen storage disease type IV patients.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

GYS1 or PPP1R3C deficiency rescues murine adult polyglucosan body disease

Chown

Wang

Zhao

et al. 2020

Ann Clin Transl Neurol

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“…Insufficient direct and indirect downregulation of chain-elongating GYS in the absence of a functional laforin-malin complex was offered as an explanation (Vilchez et al, 2007; Worby et al, 2008; Figure 1C). Increased chain lengths have also been shown in Andersen disease, a juvenile-onset GSD type IV variant, though using older limited methodology (Brown and Brown, 1966; Mercierand Whelan, 1973), and CLD has not yet been analyzed in the context of APBD. Increased chain length is a logical consequence of reduced GBE1 activity.…”

Section: Introductionmentioning

confidence: 99%

Skeletal Muscle Glycogen Chain Length Correlates with Insolubility in Mouse Models of Polyglucosan-Associated Neurodegenerative Diseases

et al. 2019

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SUMMARY Lafora disease (LD) and adult polyglucosan body disease (APBD) are glycogen storage diseases characterized by a pathogenic buildup of insoluble glycogen. Mechanisms causing glycogen insolubility are poorly understood. Here, in two mouse models of LD (Epm2a−/− and Epm2b−/−) and one of APBD (Gbe1ys/ys), the separation of soluble and insoluble muscle glycogen is described, enabling separate analysis of each fraction. Total glycogen is increased in LD and APBD mice, which, together with abnormal chain length and molecule size distributions, is largely if not fully attributed to insoluble glycogen. Soluble glycogen consists of molecules with distinct chain length distributions and differential corresponding solubility, providing a mechanistic link between soluble and insoluble glycogen in vivo. Phosphorylation states differ across glycogen fractions and mouse models, demonstrating that hyperphosphorylation is not a basic feature of insoluble glycogen. Lastly, model-specific variances in protein and activity levels of key glycogen synthesis enzymes suggest uninvestigated regulatory mechanisms.

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“…Differences in these key factors modulate glycogen solubility, accessibility to interacting enzymes, and granular size (Brewer & Gentry, 2019; Gentry et al, 2018). Multiple glycogen storage disorders (GSDs) present with increased phosphate content and/or abnormal branching and chain elongation (Brown & Brown, 1966; Mercier & Whelan, 1973; Nitschke et al, 2017; Sullivan et al, 2019). Tissue‐ and context‐specific glycogen architecture with respect to biology and disease remains a critical knowledge gap in the field.…”

Section: Brain Glycogen – Architecturementioning

confidence: 99%

The multifaceted roles of the brain glycogen

Markussen

Corti

Byrne

et al. 2023

Journal of Neurochemistry

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Glycogen is a biologically essential macromolecule that is directly involved in multiple human diseases. While its primary role in carbohydrate storage and energy metabolism in the liver and muscle is well characterized, recent research has highlighted critical metabolic and non‐metabolic roles for glycogen in the brain. In this review, the emerging roles of glycogen homeostasis in the healthy and diseased brain are discussed with a focus on advancing our understanding of the role of glycogen in the brain. Innovative technologies that have led to novel insights into glycogen functions are detailed. Key insights into how cellular localization impacts neuronal and glial function are discussed. Perturbed glycogen functions are observed in multiple disorders of the brain, including where it serves as a disease driver in the emerging category of neurological glycogen storage diseases (n‐GSDs). n‐GSDs include Lafora disease (LD), adult polyglucosan body disease (APBD), Cori disease, Glucose transporter type 1 deficiency syndrome (G1D), GSD0b, and late‐onset Pompe disease (PD). They are neurogenetic disorders characterized by aberrant glycogen which results in devastating neurological and systemic symptoms. In the most severe cases, rapid neurodegeneration coupled with dementia results in death soon after diagnosis. Finally, we discuss current treatment strategies that are currently being developed and have the potential to be of great benefit to patients with n‐GSD. Taken together, novel technologies and biological insights have resulted in a renaissance in brain glycogen that dramatically advanced our understanding of both biology and disease. Future studies are needed to expand our understanding and the multifaceted roles of glycogen and effectively apply these insights to human disease.image

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Further Characterization of Glycogen from Type‐IV Glycogen‐Storage Disease

Cited by 12 publications

References 5 publications

GYS1 or PPP1R3C deficiency rescues murine adult polyglucosan body disease

GYS1 or PPP1R3C deficiency rescues murine adult polyglucosan body disease

Skeletal Muscle Glycogen Chain Length Correlates with Insolubility in Mouse Models of Polyglucosan-Associated Neurodegenerative Diseases

The multifaceted roles of the brain glycogen

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