Mechanism suppressing glycogen synthesis in neurons and its demise in progressive myoclonus epilepsy

Vı́lchez, David; Ros, Susana; Cifuentes, Daniel; Pujadas, Lluı́s; Vallès, Jordi; García-Fojeda, Belén; Criado‐García, Olga; Fernández-Sánchez, Elena; Medraño-Fernández, Iria; Domínguez, Jorge; Garcı́a-Rocha, Mar; Soriano, Eduardo; Córdoba, Santiago Rodrı́guez de; Guinovart, Joan J.

doi:10.1038/nn1998

Cited by 319 publications

(371 citation statements)

References 42 publications

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“…20 In addition, we previously showed that neuron-specific hyperactivation of GS and the subsequent accumulation of glycogen severely compromise neuronal function and survival. 17,21 All together, these data raise the question as to why neurons express MGS if they do not accumulate the polysaccharide under normal conditions and would be unable to degrade it.…”

Section: Introductionmentioning

confidence: 99%

Neurons Have an Active Glycogen Metabolism that Contributes to Tolerance to Hypoxia

Sáez

Durán

Sinadinos

et al. 2014

J Cereb Blood Flow Metab

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172

147

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Glycogen is present in the brain, where it has been found mainly in glial cells but not in neurons. Therefore, all physiologic roles of brain glycogen have been attributed exclusively to astrocytic glycogen. Working with primary cultured neurons, as well as with genetically modified mice and flies, here we report that-against general belief-neurons contain a low but measurable amount of glycogen. Moreover, we also show that these cells express the brain isoform of glycogen phosphorylase, allowing glycogen to be fully metabolized. Most importantly, we show an active neuronal glycogen metabolism that protects cultured neurons from hypoxia-induced death and flies from hypoxia-induced stupor. Our findings change the current view of the role of glycogen in the brain and reveal that endogenous neuronal glycogen metabolism participates in the neuronal tolerance to hypoxic stress.

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Section: Introductionmentioning

confidence: 99%

Neurons Have an Active Glycogen Metabolism that Contributes to Tolerance to Hypoxia

Sáez

Durán

Sinadinos

et al. 2014

J Cereb Blood Flow Metab

Self Cite

172

147

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“…Several potential targets for malin have been proposed, including laforin (22), glycogen synthase (GS) (23), the glycogen debranching enzyme, amylo-1,6-glucosidase,4-␣-glucanotransferase (AGL) (24), and the type 1 phosphatase regulatory subunit protein targeting to glycogen (PTG) (23,25) (see "Discussion"). Candidate substrates for laforin have been more elusive.…”

mentioning

confidence: 99%

Abnormal Metabolism of Glycogen Phosphate as a Cause for Lafora Disease

Tagliabracci

Girard

Segvich

et al. 2008

Journal of Biological Chemistry

156

200

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Lafora disease is a progressive myoclonus epilepsy with onset in the teenage years followed by neurodegeneration and death within 10 years. A characteristic is the widespread formation of poorly branched, insoluble glycogen-like polymers (polyglucosan) known as Lafora bodies, which accumulate in neurons, muscle, liver, and other tissues. Approximately half of the cases of Lafora disease result from mutations in the EPM2A gene, which encodes laforin, a member of the dual specificity protein phosphatase family that is able to release the small amount of covalent phosphate normally present in glycogen. In studies of Epm2a ؊/؊ mice that lack laforin, we observed a progressive change in the properties and structure of glycogen that paralleled the formation of Lafora bodies. At three months, glycogen metabolism remained essentially normal, even though the phosphorylation of glycogen has increased 4-fold and causes altered physical properties of the polysaccharide. By 9 months, the glycogen has overaccumulated by 3-fold, has become somewhat more phosphorylated, but, more notably, is now poorly branched, is insoluble in water, and has acquired an abnormal morphology visible by electron microscopy. These glycogen molecules have a tendency to aggregate and can be recovered in the pellet after low speed centrifugation of tissue extracts. The aggregation requires the phosphorylation of glycogen. The aggregrated glycogen sequesters glycogen synthase but not other glycogen metabolizing enzymes. We propose that laforin functions to suppress excessive glycogen phosphorylation and is an essential component of the metabolism of normally structured glycogen.Glycogen is a branched polymer of glucose that acts as a repository of energy used in times of need (1). Liver and skeletal muscle contain the two largest deposits in mammals, but heart, brain, adipose, as well as many other tissues synthesize the polymer. Polymerization occurs via ␣-1,4-glycosidic linkages between glucose residues, with branch points introduced by ␣-1,6-glycosidic linkages. The frequency of branching determines the topology of glycogen and distinguishes it from the carbohydrate moiety of starch (2). A unique three-dimensional structure of glycogen cannot be determined experimentally because of the polydispersity of the molecule, but a widely accepted model of its structure has been proposed (3). Glycogen is composed of successive layers, or tiers, of glucose residues; a full size molecule consists of 12 tiers, with M r ϭ ϳ10 7 and a diameter of ϳ40 nm (4). Glycogen has been reported to contain small amounts of covalently linked phosphate, on the order of 0.064% by weight or 0.121% mol/mol (5-7). The mechanism by which the phosphate is introduced remains unclear. One suggestion (5) has been the existence of a glucose-1-phosphate transferase that would form C1-C6 bridging phosphodiesters, but this enzyme has not been further defined at the molecular level. In plant amylopectin, C1 and C3 phosphomonoesters have been shown to be formed by dikinase enzymes (8), but...

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“…Despite expressing all the necessary enzymes for glycogen synthesis, this pathway remains mostly inactive in neurons [27]. At the cellular level, glycogen biogenesis from glucose requires the sequential activities of hexokinase (glucose / glucose-6-phosphate), phosphoglucomutase (glucose-6-phosphate / glucose-1-phosphate), uridine diphosphate (UDP)-glucose pyrophosphorylase (glucose-1-phosphate / UDP-glucose) and glycogen synthase, which adds glucosyl residues from UDP-glucose to the glycogen molecule via a-(1,4) bonds.…”

Section: Brain Glycogenmentioning

confidence: 99%

Technical and experimental features of Magnetic Resonance Spectroscopy of brain glycogen metabolism

Soares

Gruetter

Lei

2017

Analytical Biochemistry

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a b s t r a c tIn the brain, glycogen is a source of glucose not only in emergency situations but also during normal brain activity. Altered brain glycogen metabolism is associated with energetic dysregulation in pathological conditions, such as diabetes or epilepsy. Both in humans and animals, brain glycogen levels have been assessed non-invasively by Carbon-13 Magnetic Resonance Spectroscopy ( 13 C-MRS) in vivo. With this approach, glycogen synthesis and degradation may be followed in real time, thereby providing valuable insights into brain glycogen dynamics. However, compared to the liver and muscle, where glycogen is abundant, the sensitivity for detection of brain glycogen by 13 C-MRS is inherently low. In this review we focus on strategies used to optimize the sensitivity for 13 C-MRS detection of glycogen. Namely, we explore several technical perspectives, such as magnetic field strength, field homogeneity, coil design, decoupling, and localization methods. Furthermore, we also address basic principles underlying the use of 13 C-labeled precursors to enhance the detectable glycogen signal, emphasizing specific experimental aspects relevant for obtaining kinetic information on brain glycogen.

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Mechanism suppressing glycogen synthesis in neurons and its demise in progressive myoclonus epilepsy

Cited by 319 publications

References 42 publications

Neurons Have an Active Glycogen Metabolism that Contributes to Tolerance to Hypoxia

Neurons Have an Active Glycogen Metabolism that Contributes to Tolerance to Hypoxia

Abnormal Metabolism of Glycogen Phosphate as a Cause for Lafora Disease

Technical and experimental features of Magnetic Resonance Spectroscopy of brain glycogen metabolism

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