Article
Clinical Neurology
Jordi Duran, Arnau Hervera, Kia H. Markussen, Olga Varea, Iliana Lopez-Soldado, Ramon C. Sun, Jose Antonio del Rio, Matthew S. Gentry, Joan J. Guinovart
Summary: Recent studies have shown that Lafora bodies are also present in astrocytes, not only in neurons. Blocking glycogen synthesis in astrocytes prevents the increase in neurodegeneration markers, autophagy impairment, and metabolic changes characteristic of the malin(KO) model.
Review
Cell Biology
Jordi Duran
Summary: Lafora disease is a rare disorder caused by mutations in the EPM2A or NHLRC1 gene, resulting in the accumulation of poorly branched glycogen known as Lafora bodies in the brain and other tissues. While it was previously believed that these glycogen aggregates only accumulated in neurons, recent research has shown that astrocytes also play a significant role in the pathology of the disease. Understanding the involvement of astrocytes in Lafora disease has important implications for other conditions characterized by abnormal glycogen accumulation in astrocytes, such as Adult Polyglucosan Body disease and Corpora amylacea buildup in aged brains.
Article
Clinical Neurology
Katherine J. Donohue, Bethany Fitzsimmons, Ronald C. Bruntz, Kia H. Markussen, Lyndsay E. A. Young, Harrison A. Clarke, Peyton T. Coburn, Laiken E. Griffith, William Sanders, Jack Klier, Sara N. Burke, Andrew P. Maurer, Berge A. Minassian, Ramon C. Sun, Holly B. Kordasiewisz, Matthew S. Gentry
Summary: Patients with Lafora disease have a mutation in EPM2A or EPM2B, leading to dysregulated glycogen metabolism and the formation of Lafora bodies. In a mouse model, reducing glycogen synthesis by 50% decreased Lafora body formation and disease phenotypes. By targeting Gys1, an antisense oligonucleotide (ASO) was able to reduce glycogen synthesis in the brain and halt disease progression.
Review
Biochemistry & Molecular Biology
Stefania Della Vecchia, Maria Marchese, Filippo Maria Santorelli
Summary: This study systematically reviewed the role of glial cells in Lafora disease (LD). The findings suggest that glial cells accumulate polyglucosan bodies (PBs) in LD and contribute to neurodegeneration and epilepsy. Future research should consider glial cells as a potential therapeutic target.
Article
Neurosciences
Olga Varea, Jordi Duran, Monica Aguilera, Neus Prats, Joan J. Guinovart
Summary: Lafora disease (LD) is a fatal adolescence-onset neurodegenerative condition characterized by the accumulation of aberrant glycogen aggregates known as Lafora bodies (LBs). Early suppression of glycogen synthase (MGS) can prevent LB formation and pathological manifestations of LD, but it is unclear whether late suppression of MGS can halt LB accumulation. Further research is needed to understand the potential therapeutic effects of targeting MGS in LD treatment.
NEUROBIOLOGY OF DISEASE
(2021)
Article
Clinical Neurology
Saija Ahonen, Silvia Nitschke, Tamar R. Grossman, Holly Kordasiewicz, Peixiang Wang, Xiaochu Zhao, Dikran R. Guisso, Sahba Kasiri, Felix Nitschke, Berge A. Minassian
Summary: Lafora disease is a fatal progressive myoclonus epilepsy caused by the accumulation of long branches in glycogen molecules leading to the formation of Lafora bodies. In mouse models, targeting the GYS1 mRNA with an antisense oligonucleotide (Gys1-ASO) prevented the formation of Lafora bodies and halted disease progression, showing promise as a potential therapy for this catastrophic epilepsy.
Article
Biochemistry & Molecular Biology
Lori Israelian, Silvia Nitschke, Peixiang Wang, Xiaochu Zhao, Ami M. Perri, Jennifer P. Y. Lee, Brandy Verhalen, Felix Nitschke, Berge A. Minassian
Summary: This study investigates the impact of eliminating different PP1 subunits, such as PPP1R3D and PPP1R3C, on the formation of Lafora bodies and glycogen metabolism in the nervous system. The research reveals that PPP1R3C is the major isoform in most tissues, while PPP1R3D plays a significant role in neurons and cardiomyocytes. These findings contribute to a better understanding of brain glycogen metabolism and Lafora disease.
JOURNAL OF NEUROCHEMISTRY
(2021)
Article
Clinical Neurology
Alessandro Orsini, Daniele Ferrari, Antonella Riva, Andrea Santangelo, Angelo Macri, Elena Freri, Laura Canafoglia, Alfredo D'Aniello, Giancarlo Di Gennaro, Gabriele Massimetti, Carlo Minetti, Federico Zara, Roberto Michelucci, Anupreet Tumber, Ajoy Vincent, Berge Arakel Minassian, Pasquale Striano
Summary: This study provides further evidence of early retinal alterations in LD patients. The degree of cones and rods dysfunction is related to disease duration.
JOURNAL OF NEUROLOGY
(2022)
Article
Developmental Biology
Marcus D. Kilwein, Matthew R. Johnson, Jonathon M. Thomalla, Anthony P. Mahowald, Michael A. Welte
Summary: Researchers have found that three major nutrients in fruit fly embryos are stored in different structures within the egg and then spatially allocated to specific tissues during embryonic development. By disrupting the embryo's ability to sort nutrients, scientists have provided evidence for the functional importance of spatial nutrient sorting.
Article
Behavioral Sciences
Kia H. Markussen, Jessica K. A. Macedo, Maria Machio, Alison Dolce, Y. Paul Goldberg, Craig W. Vander Kooi, Matthew S. Gentry
Summary: Lafora disease is a fatal childhood dementia with severe epilepsy caused by recessive mutations in EPM2A or EPM2B genes, characterized by abnormal cytoplasmic carbohydrate aggregates called Lafora bodies. The 6th International Lafora Epilepsy Workshop, held online due to the pandemic, brought together nearly 300 clinicians, scientists, and stakeholders to discuss clinical progress, translational research, and novel discoveries in understanding the mechanisms of LD.
EPILEPSY & BEHAVIOR
(2021)
Article
Clinical Neurology
Olga Varea, Joan J. Guinovart, Jordi Duran
Summary: Lafora disease is a fatal childhood dementia caused by mutations in either laforin or malin genes. Restoring malin at an advanced stage of the disease has shown to be an effective treatment.
BRAIN COMMUNICATIONS
(2022)
Article
Clinical Neurology
Antonella Riva, Alessandro Orsini, Marcello Scala, Vittoria Taramasso, Laura Canafoglia, Giuseppe d'Orsi, Maria Teresa Di Claudio, Carlo Avolio, Alfredo D'Aniello, Maurizio Elia, Silvana Franceschetti, Giancarlo Di Gennaro, Francesca Bisulli, Paolo Tinuper, Maria Tappata, Antonino Romeo, Elena Freri, Carla Marini, Cinzia Costa, Vito Sofia, Edoardo Ferlazzo, Adriana Magaudda, Pierangelo Veggiotti, Elena Gennaro, Angela Pistorio, Carlo Minetti, Amedeo Bianchi, Salvatore Striano, Roberto Michelucci, Federico Zara, Berge Arakel Minassian, Pasquale Striano
Summary: Lafora disease is a rare neurodegenerative disorder characterized by progressive myoclonus, refractory epilepsy, and cognitive deterioration. Long-term follow-up of 26 Italian patients revealed a worse prognosis in patients with EPM2A mutations, while those with EPM2B mutations showed delayed onset of symptoms, suggesting a possible influence on disease severity.
JOURNAL OF THE NEUROLOGICAL SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Jin Xue, Yingbao Zhu, Liyi Wei, Hongjing Huang, Guangxu Li, Wen Huang, Hua Zhu, Ranhui Duan
Summary: NgBR, encoded by NUS1 gene, is involved in cholesterol transport and the risk of Parkinson's disease. Knockdown of tango14, the ortholog of NUS1, in fruit flies leads to decreased locomotive abilities, loss of dopaminergic neurons, and cholesterol accumulation. This study also reveals neurodegenerative effects and increased alpha-synuclein neurotoxicity in tango14 knockdown flies.
Review
Biochemistry & Molecular Biology
Michele Brischigliaro, Erika Fernandez-Vizarra, Carlo Viscomi
Summary: The fruit fly Drosophila melanogaster is a valuable model organism for studying basic physiological processes and genetic diseases. With the availability of genetic tools, it offers insights into the mechanisms of mitochondrial diseases. Recent development of D. melanogaster models of mitochondrial disease has provided important information on molecular mechanisms and pathological consequences of mitochondrial dysfunction. This article provides an overview of these models and highlights the significance of D. melanogaster as a model for studying mitochondrial disorders.
Article
Multidisciplinary Sciences
Douglas L. Rothman, Stephen C. Stearns, Robert G. Shulman
Summary: Research indicates that during the Crabtree effect in yeast, short-term adaptation depends on the ability of the glycogen/trehalose shunt to balance the glycolytic pathway, with later gene expression of new isoforms of glycolytic enzymes providing additional homeostatic mechanisms for increased ATP production and product efficiency while maintaining glycolytic balance.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Cell Biology
Pranvera Sadiku, Joseph A. Willson, Ellise M. Ryan, David Sammut, Patricia Coelho, Emily R. Watts, Robert Grecian, Jason M. Young, Martin Bewley, Simone Arienti, Ananda S. Mirchandani, Manuel A. Sanchez Garcia, Tyler Morrison, Ailing Zhang, Leila Reyes, Tobias Griessler, Privjyot Jheeta, Gordon G. Paterson, Christopher J. Graham, John P. Thomson, Kenneth Baillie, A. A. Roger Thompson, Jessie-May Morgan, Abel Acosta-Sanchez, Veronica M. Darde, Jordi Duran, Joan J. Guinovart, Gio Rodriguez-Blanco, Alex Von Kriegsheim, Richard R. Meehan, Massimiliano Mazzone, David H. Dockrell, Bart Ghesquiere, Peter Carmeliet, Moira K. B. Whyte, Sarah R. Walmsley
Summary: Recent research has shown that neutrophils can effectively survive and kill bacteria in injured and infected tissues by generating intracellular glycogen stores through gluconeogenesis and glycogenesis. Additionally, reduced glycogen cycling in neutrophils from patients with chronic obstructive pulmonary disease may be associated with impaired function.
Article
Neurosciences
Olga Varea, Jordi Duran, Monica Aguilera, Neus Prats, Joan J. Guinovart
Summary: Lafora disease (LD) is a fatal adolescence-onset neurodegenerative condition characterized by the accumulation of aberrant glycogen aggregates known as Lafora bodies (LBs). Early suppression of glycogen synthase (MGS) can prevent LB formation and pathological manifestations of LD, but it is unclear whether late suppression of MGS can halt LB accumulation. Further research is needed to understand the potential therapeutic effects of targeting MGS in LD treatment.
NEUROBIOLOGY OF DISEASE
(2021)
Article
Clinical Neurology
Pascal Laforet, Anders Oldfors, Edoardo Malfatti, John Vissing
NEUROMUSCULAR DISORDERS
(2021)
Article
Biochemistry & Molecular Biology
Iliana Lopez-Soldado, Joan J. Guinovart, Jordi Duran
Summary: Increasing liver glycogen content can reduce the diabetic phenotype independently of circulating insulin. This strategy was validated in Akita mice, lowering blood glucose levels and food intake, restoring hepatic energy state, and normalizing gluconeogenesis and glycolysis back to nondiabetic levels.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Neurosciences
Pasquale Pellegrini, Arnau Hervera, Olga Varea, M. Kathryn Brewer, Iliana Lopez-Soldado, Anna Guitart, Monica Aguilera, Neus Prats, Jose Antonio del Rio, Joan J. Guinovart, Jordi Duran
Summary: Lafora disease (LD) is a fatal childhood-onset dementia characterized by the accumulation of glycogen aggregates in various organs, particularly in the brain. The presence of p62, an autophagy adaptor, plays a role in the formation of these aggregates, suggesting a protective mechanism to mitigate the harmful consequences of glycogen accumulation in the brain.
MOLECULAR NEUROBIOLOGY
(2022)
Article
Nutrition & Dietetics
Alvaro Olivera-Nappa, Sebastian Contreras, Maria Florencia Tevy, David Medina-Ortiz, Andres Leschot, Pilar Vigil, Carlos Conca
Summary: There is growing evidence that dietary polyphenols can be used as an early intervention for treating glucose-insulin dysregulation. A methodology using an oral glucose tolerance test (OGTT) is proposed to quantify the effects of polyphenol-rich food on glycemic regulation in individuals. This method helps identify individuals at high risk of dysglycemia and assess the effectiveness of interventions over time.
FRONTIERS IN NUTRITION
(2022)
Article
Neurosciences
Cristian Arredondo, Carolina Cefaliello, Agnieszka Dyrda, Nur Jury, Pablo Martinez, Ivan Diaz, Armando Amaro, Helene Tran, Danna Morales, Maria Pertusa, Lorelei Stoica, Elsa Fritz, Daniela Corvalan, Sebastian Abarzua, Maxs Mendez-Ruette, Paola Fernandez, Fabiola Rojas, Meenakshi Sundaram Kumar, Rodrigo Aguilar, Sandra Almeida, Alexandra Weiss, Fernando J. Bustos, Fernando Gonzalez-Nilo, Carolina Otero, Maria Florencia Tevy, Daryl A. Bosco, Juan C. Saez, Thilo Kahne, Fen-Biao Gao, James D. Berry, Katharine Nicholson, Miguel Sena-Esteves, Rodolfo Madrid, Diego Varela, Martin Montecino, Robert H. Brown, Brigitte van Zundert
Summary: Non-cell-autonomous mechanisms, specifically the release of unidentified toxic factors by astrocytes, contribute to the neurodegenerative diseases ALS and FTD. Studies found that astrocytes with ALS/FTD-related mutations display elevated levels of intracellular inorganic polyphosphate (polyP), which is also present in astrocyte-conditioned media (ACM). Degradation or neutralization of polyP in ALS/FTD astrocytes or ACM prevents the death of motoneurons. Additionally, polyP staining signals are enriched in postmortem ALS spinal cord sections and ALS cerebrospinal fluid (CSF) exhibits increased concentrations of polyP, suggesting polyP as a potential therapeutic target and biomarker for ALS/FTD.
Article
Multidisciplinary Sciences
Elena Gracia-Latorre, Lidia Perez, Mariana Muzzopappa, Marco Milan
Summary: The study reveals that the specification and regenerative capacity of the wing in Drosophila rely on a single wing-specific enhancer of the wingless gene. Within this enhancer, two evolutionary conserved cis-regulatory modules are identified to mediate these processes through distinct molecular mechanisms.
NATURE COMMUNICATIONS
(2022)
Article
Endocrinology & Metabolism
Iliana Lopez-Soldado, Joan J. Guinovart, Jordi Duran
Summary: Increased liver glycogen content can ameliorate the phenotype of obesity and diabetes, but has no effect on lipid metabolism.
FRONTIERS IN ENDOCRINOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Iliana Lopez-Soldado, Joan J. J. Guinovart, Jordi Duran
Summary: This study demonstrates that increasing liver glycogen stores can reduce appetite and improve glucose tolerance in mice fed a high-fat diet. The researchers overexpressed a non-inactivatable form of glycogen synthase specifically in the liver, resulting in increased hepatic glycogen content in mice. These mice exhibited a preserved hepatic energy state, reduced food intake, lower body weight and fat mass, and improved glucose tolerance compared to control mice.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Cell Biology
Sinthu Pathmanapan, Raymond Poon, Tomasa Barrientos De Renshaw, Puviindran Nadesan, Makoto Nakagawa, Gireesh A. Seesankar, Adrian Kwan Ho Loe, Hongyuan H. Zhang, Joan J. Guinovart, Jordi Duran, Christopher B. Newgard, Jay S. Wunder, Benjamin A. Alman
Summary: Chondrosarcomas, the most common malignancy of cartilage, are linked to genetic mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 genes. The presence of IDH mutations in enchondromas, the benign precursor lesions, suggests that these mutations occur early in the development of malignancy. Our studies on mutant IDH chondrosarcomas and mutant Idh mice have found that glycogen is deposited exclusively in mutant cells, and its utilization influences tumor cell behavior and energy pathways. The interaction between mutant IDH1 and hypoxia-inducible factor 1a (HIF1a) appears to regulate key enzymes in glycogen metabolism, suggesting a critical role for glycogen in enchondromas and chondrosarcomas.
Review
Cell Biology
Jordi Duran
Summary: Lafora disease is a rare disorder caused by mutations in the EPM2A or NHLRC1 gene, resulting in the accumulation of poorly branched glycogen known as Lafora bodies in the brain and other tissues. While it was previously believed that these glycogen aggregates only accumulated in neurons, recent research has shown that astrocytes also play a significant role in the pathology of the disease. Understanding the involvement of astrocytes in Lafora disease has important implications for other conditions characterized by abnormal glycogen accumulation in astrocytes, such as Adult Polyglucosan Body disease and Corpora amylacea buildup in aged brains.
Article
Biochemistry & Molecular Biology
M. Kathryn Brewer, Pascual Torres, Victoria Ayala, Manuel Portero-Otin, Reinald Pamplona, Pol Andres-Benito, Isidro Ferrer, Joan J. Guinovart, Jordi Duran
Summary: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron loss in the spinal cord. Glycogen accumulation in reactive astrocytes has been found to contribute to neurotoxicity and disease progression in ALS. This study demonstrates that glycogen accumulates in the spinal cord and brainstem of ALS mice and is associated with reactive astrocytes. The reduced glycogen synthesis in ALS mice leads to a longer lifespan and lower levels of pro-inflammatory cytokine Cxcl10, suggesting that glycogen accumulation is linked to inflammation and disease progression.
JOURNAL OF NEUROCHEMISTRY
(2023)
Article
Clinical Neurology
Olga Varea, Joan J. Guinovart, Jordi Duran
Summary: Lafora disease is a fatal childhood dementia caused by mutations in either laforin or malin genes. Restoring malin at an advanced stage of the disease has shown to be an effective treatment.
BRAIN COMMUNICATIONS
(2022)
Meeting Abstract
Endocrinology & Metabolism
Raymond Swanson, Muge Yemisci, Pierre Magistretti, Jordi Duran
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
(2022)
