Brain Metabolism - Lafora Disease
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Lafora disease
Lafora disease
Lafora disease (LD, OMIM #254780) is a fatal neurodegenerative condition that affects children. It starts as myoclonus epilepsy and proceeds to rapid cognitive deterioration and death within a few years. The hallmark of the disease is the accumulation of glycogen aggregates in the form of the so-called Lafora bodies (LBs), in several cell types, including the brain. Our research has demonstrated that the accumulation of these LBs underlies epilepsy, neurodegeneration and functional impairments in LD. More recently, we have identified a key role of astrocytes in the pathophysiology of the disease. Although LBs were considered to be located exclusively in neurons, we have demonstrated that astrocytes accumulate most of these aggregates and these astrocytic LBs induce neuroinflammation. Furthermore, we propose that brain glycogen accumulation contributes to other neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS) and even to physiological aging. Our aim is to further understand the mechanisms driving glycogen accumulation and toxicity, and to obtain effective treatments for Lafora disease and other neurodegenerative conditions.
Lafora disease (LD, OMIM #254780) is a fatal neurodegenerative condition that affects children. It starts as myoclonus epilepsy and proceeds to rapid cognitive deterioration and death within a few years. The hallmark of the disease is the accumulation of glycogen aggregates in the form of the so-called Lafora bodies (LBs), in several cell types, including the brain. Our research has demonstrated that the accumulation of these LBs underlies epilepsy, neurodegeneration and functional impairments in LD. More recently, we have identified a key role of astrocytes in the pathophysiology of the disease. Although LBs were considered to be located exclusively in neurons, we have demonstrated that astrocytes accumulate most of these aggregates and these astrocytic LBs induce neuroinflammation. Furthermore, we propose that brain glycogen accumulation contributes to other neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS) and even to physiological aging. Our aim is to further understand the mechanisms driving glycogen accumulation and toxicity, and to obtain effective treatments for Lafora disease and other neurodegenerative conditions.
Highlighted articles for this topic
Highlighted articles for this topic
Therapeutic Window for the Treatment of Lafora Disease
Varea O, Guinovart JJ, Duran J
Jasper's Basic Mechanisms of the Epilepsies. 2024. doi: https://doi.org/10.1093/med/9780197549469.003.0053
Glycogen accumulation modulates life span in a mouse model of amyotrophic lateral sclerosis
M. Kathryn Brewer, Pascual Torres, Victòria Ayala, Manuel Portero-Otin, Reinald Pamplona, Pol Andrés-Benito, Isidro Ferrer, Joan J. Guinovart, Duran J
Journal of Neurochemistry. 2023 Jul 4. doi: https://doi.org/10.1111/jnc.15906
Role of Astrocytes in the Pathophysiology of Lafora Disease and Other Glycogen Storage Disorders
Duran J
Cells. 2023, 12(5), 722. doi: https://doi.org/10.3390/cells12050722
Malin restoration as proof of concept for gene therapy for Lafora disease.
Varea O, Guinovart JJ, Duran J.
Brain Commun. 2022 Jun 23;4(4):fcac168. doi: https://doi.org/10.1093/braincomms/fcac168
PMID: 35813879
Lack of p62 Impairs Glycogen Aggregation and Exacerbates Pathology in a Mouse Model of Myoclonic Epilepsy of Lafora.
Pellegrini P, Hervera A, Varea O, Brewer MK, López-Soldado I, Guitart A, Aguilera M, Prats N, Del Río JA, Guinovart JJ, Duran J.
Mol Neurobiol. 2022 Feb;59(2):1214-1229. doi: https://doi.org/10.1007/s12035-021-02682-6
PMID: 34962634
Astrocytic glycogen accumulation drives the pathophysiology of neurodegeneration in Lafora disease.
Duran J*, Hervera A, Markussen KH, Varea O, López-Soldado I, Sun RC, del Río JA, Gentry MS, Guinovart JJ
Brain. 2021 Sep 4;144(8):2349-2360. doi: https://doi.org/10.1093/brain/awab110
PMID: 33822008
*corresponding author
Suppression of glycogen synthesis as a treatment for Lafora disease: Establishing the window of opportunity.
Varea O, Duran J*, Aguilera M, Prats N, Guinovart JJ.
Neurobiol Dis. 2020 Nov 7;147:105173. doi: https://doi.org/10.1016/j.nbd.2020.105173
PMID: 33171226
*corresponding author
Glycogen in Astrocytes and Neurons: Physiological and Pathological Aspects.
Duran J, Gruart A, López-Ramos JC, Delgado-García JM, Guinovart JJ.
Adv Neurobiol. 2019;23:311-329. doi: https://doi.org/10.1007/978-3-030-27480-1_10
PMID: 31667813
Exploring the elusive composition of corpora amylacea of human brain. Augé E, Duran J, Guinovart JJ, Pelegrí C, Vilaplana J.
Sci Rep. 2018 Sep 10;8(1):13525. doi: https://doi.org/10.1038/s41598-018-31766-y
PMID: 30202002
Astrocytes and neurons produce distinct types of polyglucosan bodies in Lafora disease.
Augé E, Pelegrí C, Manich G, Cabezón I, Guinovart JJ, Duran J*, Vilaplana J*.
Glia. 2018 Oct;66(10):2094-2107. doi: https://doi.org/10.1002/glia.23463
PMID: 30152044
*corresponding authors
Brain glycogen in health and disease.
Duran J, Guinovart JJ.
Mol Aspects Med. 2015 Dec;46:70-7. doi: https://doi.org/10.1016/j.mam.2015.08.007
PMID: 26344371
Role of brain glycogen in the response to hypoxia and in the susceptibility to epilepsy
López-Ramos JC*, Duran J*, Gruart A, Guinovart JJ, Delgado-García JM.
Front Cell Neurosci. 2015 Oct 27;9:431. doi: https://doi.org/10.3389/fncel.2015.00431
PMID: 26578889
* co-authors
Neuronal glycogen synthesis contributes to physiological aging.
Sinadinos C, Valles-Ortega J, Boulan L, Solsona E, Tevy MF, Marquez M, Duran J, Lopez-Iglesias C, Calbó J, Blasco E, Pumarola M, Milán M, Guinovart JJ.
Aging Cell. 2014 Oct;13(5):935-45. doi: https://doi.org/10.1111/acel.12254
PMID: 25059425
Glycogen accumulation underlies neurodegeneration and autophagy impairment in Lafora disease.
Duran J, Gruart A, García-Rocha M, Delgado-García JM, Guinovart J.
Hum Mol Genet. 2014 Jun 15;23(12):3147-56. doi: https://doi.org/10.1093/hmg/ddu024
PMID: 24452334
Deleterious effects of neuronal accumulation of glycogen in flies and mice.
Duran J, Tevy MF, Garcia-Rocha M, Calbó J, Milán M, Guinovart JJ.
EMBO Mol Med. 2012 Aug;4(8):719-29. doi: https://10.1002/emmm.201200241
PMID: 22549942
Neurodegeneration and functional impairments associated with glycogen synthase accumulation in a mouse model of Lafora disease.
Valles-Ortega J*, Duran J*, Garcia-Rocha M, Bosch C, Saez I, Pujadas L, Serafin A, Cañas X, Soriano E, Delgado-García JM, Gruart A, Guinovart JJ.
EMBO Mol Med. 2011 Nov;3(11):667-81. doi: https://doi.org/10.1002/emmm.201100174
PMID: 21882344
* co-authors
Physiological roles of brain glycogen metabolism
Physiological roles of brain glycogen metabolism
Our interest is also to understand the physiological roles of brain glycogen metabolism. Glycogen concentration in the brain is relatively low compared to that found in other tissues. Although traditionally considered as an emergency energetic reservoir, we have demonstrated that glycogen plays a key role in the normal functioning of the brain. We demonstrated the importance of brain glycogen in the proper acquisition of memory and learning, as well as in the prevention of epileptic seizures. Furthermore, we have shown that, against general belief, neurons have an active glycogen metabolism that contributes to neuronal function. We have also analyzed the specific roles of astrocytic glycogen, which surprisingly is essential for synaptic plasticity but not for seizure susceptibility. We aim to further decipher the cell-type specific roles of glycogen in the central nervous system.
Our interest is also to understand the physiological roles of brain glycogen metabolism. Glycogen concentration in the brain is relatively low compared to that found in other tissues. Although traditionally considered as an emergency energetic reservoir, we have demonstrated that glycogen plays a key role in the normal functioning of the brain. We demonstrated the importance of brain glycogen in the proper acquisition of memory and learning, as well as in the prevention of epileptic seizures. Furthermore, we have shown that, against general belief, neurons have an active glycogen metabolism that contributes to neuronal function. We have also analyzed the specific roles of astrocytic glycogen, which surprisingly is essential for synaptic plasticity but not for seizure susceptibility. We aim to further decipher the cell-type specific roles of glycogen in the central nervous system.
Highlighted articles for this topic
Highlighted articles for this topic
Brain energy metabolism: A roadmap for future research.
Rae CD, Baur JA, Borges K, Dienel G, Díaz-García CM, Douglass SR, Drew K, Duarte JMN, Duran J, et al.
J Neurochem. 2024 Jan 6. https://doi.org/10.1111/jnc.16032
PMID: 38183680
Lack of Astrocytic Glycogen Alters Synaptic Plasticity but Not Seizure Susceptibility.
Duran J*, Brewer MK, Hervera A, Gruart A, Del Rio JA, Delgado-García JM, Guinovart JJ.
Mol Neurobiol. 2020 Nov;57(11):4657-4666. doi: https://doi.org/10.1007/s12035-020-02055-5
PMID: 32770452
*corresponding author
Arousal-induced cortical activity triggers lactate release from astrocytes.
Zuend M, Saab AS, Wyss MT, Ferrari KD, Hösli L, Looser ZJ, Stobart JL, Duran J, Guinovart JJ, Barros LF and Weber B.
Nat Metab. 2020; 2:179–191. doi: https://doi.org/10.1038/s42255-020-0170-4
PMID: 32694692
Glycogen in Astrocytes and Neurons: Physiological and Pathological Aspects.
Duran J, Gruart A, López-Ramos JC, Delgado-García JM, Guinovart JJ.
Adv Neurobiol. 2019;23:311-329. doi: https://doi.org/10.1007/978-3-030-27480-1_10
PMID: 31667813
Lack of Neuronal Glycogen Impairs Memory Formation and Learning-Dependent Synaptic Plasticity in Mice.
Duran J, Gruart A, Varea O, López-Soldado I, Delgado-García JM, Guinovart JJ.
Front Cell Neurosci. 2019 Aug 13;13:374. doi: https://doi.org/10.3389/fncel.2019.00374
PMID: 31456667
Brain glycogen in health and disease.
Duran J, Guinovart JJ.
Mol Aspects Med. 2015 Dec;46:70-7. doi: https://doi.org/10.1016/j.mam.2015.08.007
PMID: 26344371
Role of brain glycogen in the response to hypoxia and in the susceptibility to epilepsy
López-Ramos JC*, Duran J*, Gruart A, Guinovart JJ, Delgado-García JM.
Front Cell Neurosci. 2015 Oct 27;9:431. doi: https://doi.org/10.3389/fncel.2015.00431
PMID: 26578889
* co-authors
Neurons have an active glycogen metabolism that contributes to tolerance to hypoxia
Saez I, Duran J, Sinadinos C, Yanes O, Martínez-Pons C, Tevy F, Milan M, Guinovart J.
J Cereb Blood Flow Metab. 2014 Jun;34(6):945-55 doi: https://doi.org/10.1038/jcbfm.2014.33
PMID: 24569689
Impairment in long-term memory formation and learning-dependent synaptic plasticity in mice lacking Glycogen Synthase in the brain.
Duran J, Saez I, Gruart A, Guinovart JJ, Delgado-García JM.
J Cereb Blood Flow Metab. 2013 Apr;33(4):550-6. doi: https://doi.org/10.1038/jcbfm.2012.200
PMID: 23281428
Other contributions in the field of glycogen metabolism
Other contributions in the field of glycogen metabolism
Regarding liver glycogen, we have studied its impact on glucose homeostasis and food intake. Our results show that liver glycogen accumulation causes a reduction in food intake, protects against the deleterious effects of a high-fat diet, diminishes the metabolic impact of fasting and enhances exercise capacity.
Regarding liver glycogen, we have studied its impact on glucose homeostasis and food intake. Our results show that liver glycogen accumulation causes a reduction in food intake, protects against the deleterious effects of a high-fat diet, diminishes the metabolic impact of fasting and enhances exercise capacity.
Regarding the role of glycogenin in glycogen metabolism, this protein was thought to be essential for glycogen synthesis, since it acts as the glycogen primer that glycogen synthase elongates. However, we demonstrated that glycogenin-deficient animals are able to synthesize glycogen. These animals allowed us to identify a role of glycogen metabolism in respiratory distress syndrome. We also contributed to the study of glycogen metabolism in other tissues like the skeletal muscle or the beta cell.
Regarding the role of glycogenin in glycogen metabolism, this protein was thought to be essential for glycogen synthesis, since it acts as the glycogen primer that glycogen synthase elongates. However, we demonstrated that glycogenin-deficient animals are able to synthesize glycogen. These animals allowed us to identify a role of glycogen metabolism in respiratory distress syndrome. We also contributed to the study of glycogen metabolism in other tissues like the skeletal muscle or the beta cell.
Highlighted articles for this topic
Highlighted articles for this topic
Active Glycogen Synthase in the Liver Prevents High-Fat Diet-Induced Glucose Intolerance, Decreases Food Intake, and Lowers Body Weight.
López-Soldado I, Guinovart JJ, Duran J.
Int J Mol Sci. 2023 Jan 29;24(3):2574. doi: https://doi.org/10.3390/ijms24032574
PMID: 36768897
Hepatic overexpression of protein targeting to glycogen attenuates obesity and improves hyperglycemia in db/db mice.
López-Soldado I, Guinovart JJ, Duran J.
Front Endocrinol (Lausanne). 2022 Sep 9;13:969924. doi: https://doi.org/10.3389/fendo.2022.969924
PMID: 36157460
Increased liver glycogen levels enhance exercise capacity in mice.
López-Soldado I, Guinovart JJ, Duran J.
J Biol Chem. 2021 Aug;297(2):100976. doi: https://doi.org/10.1016/j.jbc.2021.100976
PMID: 34284060
Increasing hepatic glycogen reduces the diabetic phenotype in Akita mice
López-Soldado I, Guinovart JJ, Duran J
JBC. 2021 Mar 2;296:100498. doi: https://doi.org/10.1016/j.jbc.2021.100498
PMID: 33667544
Pulmonary glycogen deficiency as a new potential cause of Respiratory Distress Syndrome.
Testoni G, Olmeda B, Duran J, López-Rodríguez E, Aguilera M, Hernández-Álvarez MI, Prats N, Pérez-Gil J, Guinovart JJ.
Hum Mol Genet. 2021 Jan 6;29(21):3554-3565. doi: https://doi.org/10.1093/hmg/ddaa249
PMID: 33219378
Maintenance of liver glycogen during long-term fasting preserves energy state in mice.
López-Soldado I, Bertini A, Adrover A, Duran J, Guinovart JJ.
FEBS Letters. 2020 Jun;594(11):1698-1710. doi: https://doi.org/10.1002/1873-3468.13770
PMID: 32159852
Lack of glycogenin causes glycogen accumulation and muscle function impairment
Testoni G, Duran J, García-Rocha M, Vilaplana F, Serrano AL, Sebastián D, Lopez-Soldado I, Sullivan MA, Slebe F, Vilaseca M, Muñoz-Cánoves P, Guinovart JJ.
Cell Metabolism. 2017 Jul 5;26(1):256-266.e4. doi: https://doi.org/10.1016/j.cmet.2017.06.008
PMID: 28683291
Effects of hepatic glycogen on food intake and glucose homeostasis are mediated by the vagus nerve in mice.
López-Soldado I, Fuentes-Romero R, Duran J, Guinovart JJ.
Diabetologia. 2017 Jun;60(6):1076-1083. doi: https://doi.org/10.1007/s00125-017-4240-4
PMID: 28299379
Differential glucose metabolism in mice and humans affected by McArdle disease.
Krag TO, Pinós T, Nielsen TL, Duran J, García-Rocha M, Andreu AL, Vissing J.
Am J Physiol Regul Integr Comp Physiol. 2016 Aug 1;311(2):R307-14. doi: http://doi.org/10.1152/ajpregu.00489.2015
PMID: 27280431
Genetic models rule out a major role of beta cell glycogen in the control of glucose homeostasis.
Mir-Coll J, Duran J, Slebe F, García-Rocha M,Gomis R,Gasa R, Guinovart JJ.
Diabetologia. 2016 May;59(5):1012-20. doi: https://doi.org/10.1007/s00125-016-3871-1
PMID: 26825527
Liver glycogen reduces food intake and attenuates obesity in a high-fat diet-fed mouse model.
López-Soldado I, Zafra D, Duran J, Adrover A, Calbó J, Guinovart JJ.
Diabetes. 2015 Mar;64(3):796-807. doi: https://doi.org/10.2337/db14-0728
PMID: 25277398
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