Increased Laforin and Laforin Binding to Glycogen Underlie Lafora Body Formation in Malin-deficient Lafora Disease

Tiberia, Erica; Turnbull, Julie; Wang, Tony; Ruggieri, Alessandra; Zhao, Xiao Chu; Pencea, Nela; Israelian, Johan; Wang, Yin; Ackerley, Cameron; Wang, Peixiang; Liu, Yan; Minassian, Berge A.

doi:10.1074/jbc.m111.331611

Cited by 43 publications

(31 citation statements)

References 37 publications

(67 reference statements)

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“…Precisely why GS2 and PTG lead to normal glycogen rather than PBs is unclear, but in any case it is clear that increased GS1 is associated with PB formation. This result is consistent with the massive presence of GS1, and no other tested enzymes of glycogen metabolism, in LB isolated from mouse models of LD (10, 31, 34, 36-37). …”

Section: Resultssupporting

confidence: 88%

Laforin Prevents Stress-Induced Polyglucosan Body Formation and Lafora Disease Progression in Neurons

Wang

et al. 2013

Mol Neurobiol

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Glycogen, the largest cytosolic macromolecule, is soluble because of intricate construction generating perfect hydrophilic-surfaced spheres. Little is known about neuronal glycogen function and metabolism, though progress is accruing through the neurodegenerative epilepsy Lafora disease (LD) proteins laforin and malin. Neurons in LD exhibit Lafora bodies (LBs), large accumulations of malconstructed insoluble glycogen (polyglucosans). We demonstrated that the laforin-malin complex reduces LBs and protects neuronal cells against endoplasmic reticulum stress-induced apoptosis. We now show that stress induces polyglucosan formation in normal neurons in culture and in brain. This is mediated by increased glucose-6-phosphate allosterically hyperactivating muscle glycogen synthase (GS1), and is followed by activation of the glycogen digesting enzyme glycogen phosphorylase. In the absence of laforin, stress-induced polyglucosans are undigested and accumulate into massive LBs, and in laforin-deficient mice stress drastically accelerates LB accumulation and LD. The mechanism through which laforin-malin mediates polyglucosan degradation remains unclear but involves GS1 dephosphorylation by laforin. Our work uncovers the presence of rapid polyglucosan metabolism as part of the normal physiology of neuroprotection. We propose that deficiency in the degradative phase of this metabolism, leading to LB accumulation and resultant seizure predisposition and neurodegeneration, underlies LD.

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Section: Resultssupporting

confidence: 88%

Laforin Prevents Stress-Induced Polyglucosan Body Formation and Lafora Disease Progression in Neurons

Wang

et al. 2013

Mol Neurobiol

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“…Studies in LD mouse models revealed the presence of higher levels of covalently bound phosphate in LD muscle and brain glycogen (Nitschke et al, 2013, 2017; Tagliabracci et al, 2007). This is not surprising in laforin (phosphatase)-deficient Epm2a −/− mice but is intriguing in malin-deficient Epm2b −/− mice, where glycogen phosphate levels are intermediate between wild-type (WT) and Epm2a −/− levels (DePaoli-Roach et al, 2015; Tiberia et al, 2012). Increased phosphate has been hypothesized to be inseparably associated with the cause(s) of glycogen insolubility and precipitation in LD (Roach, 2015).…”

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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“…In Lafora disease there is evidence that lack of laforin, which functions to remove phosphate from glycogen, or deficient removal of laforin from glycogen by malin makes the glycogen prone to aggregation as polyglucosan (Tiberia et al 2012). An imbalance of the activities of branching enzyme and glycogen synthase has been proposed as important for polyglucosan formation in equine polysaccharide storage myopathy (PSSM1) that is due to hyper-activity of glycogen synthase ( GYS1 ) secondary to a dominant missense variant (McCue et al 2008).…”

Section: Discussionmentioning

confidence: 99%

Cardiomyopathy as presenting sign of glycogenin‐1 deficiency—report of three cases and review of the literature

Hedberg‐Oldfors

Glamuzina

Ruygrok

et al. 2016

J of Inher Metab Disea

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We describe a new type of cardiomyopathy caused by a mutation in the glycogenin-1 gene (GYG1). Three unrelated male patients aged 34 to 52 years with cardiomyopathy and abnormal glycogen storage on endomyocardial biopsy were homozygous for the missense mutation p.Asp102His in GYG1. The mutated glycogenin-1 protein was expressed in cardiac tissue but had lost its ability to autoglucosylate as demonstrated by an in vitro assay and western blot analysis. It was therefore unable to form the primer for normal glycogen synthesis. Two of the patients showed similar patterns of heart dilatation, reduced ejection fraction and extensive late gadolinium enhancement on cardiac magnetic resonance imaging. These two patients were severely affected, necessitating cardiac transplantation. The cardiomyocyte storage material was characterized by large inclusions of periodic acid and Schiff positive material that was partly resistant to alpha-amylase treatment consistent with polyglucosan. The storage material had, unlike normal glycogen, a partly fibrillar structure by electron microscopy. None of the patients showed signs or symptoms of muscle weakness but a skeletal muscle biopsy in one case revealed muscle fibres with abnormal glycogen storage. Glycogenin-1 deficiency is known as a rare cause of skeletal muscle glycogen storage disease, usually without cardiomyopathy. We demonstrate that it may also be the cause of severe cardiomyopathy and cardiac failure without skeletal muscle weakness. GYG1 should be included in cardiomyopathy gene panels.Electronic supplementary materialThe online version of this article (doi:10.1007/s10545-016-9978-1) contains supplementary material, which is available to authorized users.

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Increased Laforin and Laforin Binding to Glycogen Underlie Lafora Body Formation in Malin-deficient Lafora Disease

Cited by 43 publications

References 37 publications

Laforin Prevents Stress-Induced Polyglucosan Body Formation and Lafora Disease Progression in Neurons

Laforin Prevents Stress-Induced Polyglucosan Body Formation and Lafora Disease Progression in Neurons

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

Cardiomyopathy as presenting sign of glycogenin‐1 deficiency—report of three cases and review of the literature

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