Glycogenic activity of R6, a protein phosphatase 1 regulatory subunit, is modulated by the laforin–malin complex

Rubio-Villena, Carla; García-Gimeno, Maria Adelaida; Sanz, Pascual

doi:10.1016/j.biocel.2013.04.019

Cited by 39 publications

(32 citation statements)

References 25 publications

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“…pCMV-6xHis-ubiquitin, pHA-malin, pFlag-malin, pHA-laforin and pFlag-laforin plasmids have been previously described [26]. pCMV-HA-Nedd4.2 plasmid was from Dr. Lynne Yenush (Instituto de Biologia Molecular y Celular de Plantas, CSIC, Valencia, Spain).…”

Section: - Materials and Methodsmentioning

confidence: 99%

Homeostasis of the astrocytic glutamate transporter GLT-1 is altered in mouse models of Lafora disease

Muñoz‐Ballester¹,

Berthier²,

Viana³

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Lafora disease (LD, OMIM 254780) is a fatal rare disorder characterized by epilepsy and neurodegeneration. Although in recent years a lot of information has been gained on the molecular basis of the neurodegeneration that accompanies LD, the molecular basis of epilepsy is poorly understood. Here, we present evidence indicating that the homeostasis of glutamate transporter GLT-1 (EAAT2) is compromised in mouse models of LD. Our results indicate that primary astrocytes from LD mice have reduced capacity of glutamate transport, probably because they present a reduction in the levels of the glutamate transporter at the plasma membrane. On the other hand, the overexpression in cellular models of laforin and malin, the two proteins related to LD, results in an accumulation of GLT-1 (EAAT2) at the plasma membrane and in a severe reduction of the ubiquitination of the transporter. All these results suggest that the laforin/malin complex slows down the endocytic recycling of the GLT-1 (EAAT2) transporter. Since, defects in the function of this transporter lead to excitotoxicity and epilepsy, we suggest that the epilepsy that accompanies LD could be due, at least in part, to deficiencies in the function of the GLT-1 (EAAT2) transporter.

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Section: - Materials and Methodsmentioning

confidence: 99%

Homeostasis of the astrocytic glutamate transporter GLT-1 is altered in mouse models of Lafora disease

Muñoz‐Ballester¹,

Berthier²,

Viana³

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…However, the role of these two proteins in LD has remained elusive despite the accumulation of experimental data regarding the function of laforin and malin, the identification of alterations in various cell processes and the availability of several animal and cell models of the disease. Laforin and malin form a functional complex, which has been demonstrated to regulate the activity of proteins involved in glycogen synthesis [2][3][4][5], and laforin is the only human phosphatase able to dephosphorylate complex glucans [6,7]. Therefore, for several years LD has been linked to aberrant glycogen accumulation in neurons, in the so-called Lafora Bodies (LBs).…”

Section: Introductionmentioning

confidence: 99%

Increased Oxidative Stress and Impaired Antioxidant Response in Lafora Disease

et al. 2014

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Lafora disease (LD, OMIM 254780, ORPHA501) is a fatal neurodegenerative disorder characterized by the presence of glycogen-like intracellular inclusions called Lafora bodies and caused, in the vast majority of cases, by mutations in either EPM2A or EPM2B genes, encoding respectively laforin and malin. In the last years, several reports have revealed molecular details of these two proteins and have identified several processes affected in LD, but the pathophysiology of the disease still remains largely unknown. Since autophagy impairment has been reported as a characteristic treat in both Lafora disease cell and animal models, and as there is a link between autophagy and mitochondrial performance, we sought to determine if mitochondrial function could be altered in those models. Using fibroblasts from LD patients, deficient in laforin or malin, we found mitochondrial alterations, oxidative stress and a deficiency in antioxidant enzymes involved in the detoxification of reactive oxygen species (ROS). Similar results were obtained in brain tissue samples from transgenic mice deficient in either the EPM2A or EPM2B genes. Furthermore, in a proteomic analysis of brain tissue obtained from Epm2b-/- mice, we observed an increase in a modified form of peroxiredoxin-6, an antioxidant enzyme involved in other neurological pathologies, thus corroborating an alteration of the redox condition. These data support that oxidative stress produced by an increase in ROS production and an impairment of the antioxidant enzyme response to this stress play an important role in development of LD.

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“…PPP1R3C (PPP1R5) is expressed in many tissues and mice with heterozygous deletion of PPP1R3C had reduced glycogen levels in many tissues, accompanied by progressive glucose intolerance, hyperinsulinemia, and insulin resistance with aging (16). PPP1R3D (PPP1R6) is mainly expressed in the brain and likely plays a function in glycogen accumulation in neurons (17). PPP1R3E is highly expressed in the liver and heart muscle in rodents (18).…”

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Regulation of Glucose Homeostasis and Lipid Metabolism by PPP1R3G-mediated Hepatic Glycogenesis

Zhang

Huang

et al. 2014

Molecular Endocrinology

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Liver glycogen metabolism plays an important role in glucose homeostasis. Glycogen synthesis is mainly regulated by glycogen synthase that is dephosphorylated and activated by protein phosphatase 1 (PP1) in combination with glycogen-targeting subunits or G subunits. There are seven G subunits (PPP1R3A to G) that control glycogenesis in different organs. PPP1R3G is a recently discovered G subunit whose expression is changed along the fasting-feeding cycle and is proposed to play a role in postprandial glucose homeostasis. In this study, we analyzed the physiological function of PPP1R3G using a mouse model with liver-specific overexpression of PPP1R3G. PPP1R3G overexpression increases hepatic glycogen accumulation, stimulates glycogen synthase activity, elevates fasting blood glucose level, and accelerates postprandial blood glucose clearance. In addition, the transgenic mice have a reduced fat composition, together with decreased hepatic triglyceride level. Fasting-induced hepatic steatosis is relieved by PPP1R3G overexpression. In addition, PPP1R3G overexpression is able to elevate glycogenesis in primary hepatocytes. The glycogen-binding domain is indispensable for the physiological activities of PPP1R3G on glucose metabolism and triglyceride accumulation in the liver. Cumulatively, these data indicate that PPP1R3G plays a critical role in postprandial glucose homeostasis and liver triglyceride metabolism via its regulation on hepatic glycogenesis.

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Glycogenic activity of R6, a protein phosphatase 1 regulatory subunit, is modulated by the laforin–malin complex

Cited by 39 publications

References 25 publications

Homeostasis of the astrocytic glutamate transporter GLT-1 is altered in mouse models of Lafora disease

Homeostasis of the astrocytic glutamate transporter GLT-1 is altered in mouse models of Lafora disease

Increased Oxidative Stress and Impaired Antioxidant Response in Lafora Disease

Regulation of Glucose Homeostasis and Lipid Metabolism by PPP1R3G-mediated Hepatic Glycogenesis

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