Regulation of glycogen synthesis by the laforin–malin complex is modulated by the AMP-activated protein kinase pathway

Solaz-Fuster, Maria del Carmen; Gimeno-Alcañíz, José V.; Ros, Susana; Fernández-Sánchez, Maria Elena; García-Fojeda, Belén; Criado‐García, Olga; Vı́lchez, David; Domínguez, Jorge; Garcı́a-Rocha, Mar; Sánchez-Piris, Maribel; Aguado, Carmen; Knecht, Erwin; Serratosa, Joan; Guinovart, Joan J.; Sanz, Pascual; Córdoba, Santiago Rodrı́guez de

doi:10.1093/hmg/ddm339

Cited by 128 publications

(209 citation statements)

References 62 publications

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“…Neuronal glycogen may be important for promoting neuronal survival under pathological conditions, such as oxidative stress and hypoxia (65). However, the neurons could be able to use but not accumulate glycogen because this process has been related with neuronal death in some pathologies (66,67). The effect of the Wnt3a ligand on glycogen synthesis in neurons requires further study.…”

Section: Wnt Signaling Stimulates Glucose Utilization In Neuronsmentioning

confidence: 99%

Activation of Wnt Signaling in Cortical Neurons Enhances Glucose Utilization through Glycolysis

Cisternas

Salazar

Silva-Álvarez

et al. 2016

Journal of Biological Chemistry

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Edited by Jeffrey E. PessinThe Wnt signaling pathway is critical for a number of functions in the central nervous system, including regulation of the synaptic cleft structure and neuroprotection against injury. Deregulation of Wnt signaling has been associated with several brain pathologies, including Alzheimer's disease. In recent years, it has been suggested that the Wnt pathway might act as a central integrator of metabolic signals from peripheral organs to the brain, which would represent a new role for Wnt signaling in cell metabolism. Energy metabolism is critical for normal neuronal function, which mainly depends on glucose utilization. Brain energy metabolism is important in almost all neurological disorders, to which a decrease in the capacity of the brain to utilize glucose has been linked. However, little is known about the relationship between Wnt signaling and neuronal glucose metabolism in the cellular context. In the present study, we found that acute treatment with the Wnt3a ligand induced a large increase in glucose uptake, without changes in the expression or localization of glucose transporter type 3. In addition, we observed that Wnt3a treatment increased the activation of the metabolic sensor Akt. Moreover, we observed an increase in the activity of hexokinase and in the glycolytic rate, and both processes were dependent on activation of the Akt pathway. Furthermore, we did not observe changes in the activity of glucose-6-phosphate dehydrogenase or in the pentose phosphate pathway. The effect of Wnt3a was independent of both the transcription of Wnt target genes and synaptic effects of Wnt3a. Together, our results suggest that Wnt signaling stimulates glucose utilization in cortical neurons through glycolysis to satisfy the high energy demand of these cells.

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Section: Wnt Signaling Stimulates Glucose Utilization In Neuronsmentioning

confidence: 99%

Activation of Wnt Signaling in Cortical Neurons Enhances Glucose Utilization through Glycolysis

Cisternas

Salazar

Silva-Álvarez

et al. 2016

Journal of Biological Chemistry

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“…Lohi et al (46) proposed that a malin⅐laforin⅐GS complex forms and is targeted for degradation. In studies of hepatocytes (50) and neurons (23), the groups of Guinovart and de Cordoba proposed that a malin⅐laforin complex ubiquitylated the type 1 phosphatase regulatory subunit PTG and, in neurons, also GS, leading to their degradation. Worby et al (25) also reported that malin targets PTG for degradation in a laforindependent manner.…”

Section: Figure 5 Fractionation Of Glycogen From 9 -12-month-old Epm2amentioning

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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“…It is evident from this compilation that not all aspects of the protein function are tested for each mutation, and that sensitive assays for checking the effect of mutations on the proteins function are yet to be developed. For example, the RING domain mutation in malin, p.C26S, was shown to affect the interaction between laforin and malin in a yeast two-hybrid screen [Solaz-Fuster et al, 2008]; however, the same could not be replicated in mammalian cell line studies [Dubey and Ganesh, 2008;Gentry et al, 2005].…”

Section: Functional Impact Of Ld-associated Missense Mutationsmentioning

confidence: 99%

“…Thus, defects in either malin or laforin would lead to impairment in the proteolytic processes and the symptoms of LD [Mittal et al, 2007]. Validating this hypothesis, two groups have independently shown that the laforin-malin complex promotes the degradation of protein targeting to glycogen, PTG [Solaz-Fuster et al, 2008;Worby et al, 2008] (see Fig. 1).…”

Section: Introductionmentioning

confidence: 97%

Lafora progressive myoclonus epilepsy: A meta-analysis of reported mutations in the first decade following the discovery of theEPM2AandNHLRC1genes

2009

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Lafora disease (LD) is an autosomal recessive and fatal form of progressive myoclonus epilepsy. LD patients manifest myoclonus and tonic-clonic seizures, visual hallucinations, and progressive neurologic deterioration beginning at 12 to 15 years of age. The two genes known to be associated with LD are EPM2A and NHLRC1. Mutations in at least one other as yet unknown gene also cause LD. The EMP2A encodes a protein phosphatase and NHLRC1 encodes an ubiquitin ligase. These two proteins interact with each other and, as a complex, are thought to regulate critical neuronal functions. Nearly 100 distinct mutations have been discovered in the two genes in over 200 independent LD families. Nearly half of them are missense mutations, and the deletion mutations account for one-quarter. Several reports have provided functional data for the mutant proteins and a few also provide genotype-phenotype correlations. In this review we provide an update on the spectrum of EPM2A and NHLRC1 mutations, and discuss their distribution in the patient population, genotype-phenotype correlations, and on the possible effect of disease mutations on the cellular functions of LD proteins.

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Regulation of glycogen synthesis by the laforin–malin complex is modulated by the AMP-activated protein kinase pathway

Cited by 128 publications

References 62 publications

Activation of Wnt Signaling in Cortical Neurons Enhances Glucose Utilization through Glycolysis

Activation of Wnt Signaling in Cortical Neurons Enhances Glucose Utilization through Glycolysis

Abnormal Metabolism of Glycogen Phosphate as a Cause for Lafora Disease

Lafora progressive myoclonus epilepsy: A meta-analysis of reported mutations in the first decade following the discovery of theEPM2AandNHLRC1genes

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