scholarly journals Inhibiting glycogen synthesis prevents lafora disease in a mouse model

2013 ◽  
pp. n/a-n/a ◽  
Author(s):  
Bartholomew A Pederson ◽  
Julie Turnbull ◽  
Jonathan R Epp ◽  
Staci A Weaver ◽  
Xiaochu Zhao ◽  
...  
Keyword(s):  
Mouse Model ◽  
Glycogen Synthesis ◽  
Lafora Disease

Astrocytic glycogen accumulation drives the pathophysiology of neurodegeneration in Lafora disease

Brain ◽  
2021 ◽  
Author(s):  
Jordi Duran ◽  
Arnau Hervera ◽  
Kia H Markussen ◽  
Olga Varea ◽  
Iliana López-Soldado ◽  
...  
Keyword(s):  
Mouse Model ◽  
Neurodegenerative Disorder ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Glycogen Metabolism ◽  
Cell Type ◽  
Lafora Disease ◽  
Glycogen Accumulation ◽  
Lafora Bodies

Abstract The hallmark of Lafora disease, a fatal neurodegenerative disorder, is the accumulation of intracellular glycogen aggregates, called Lafora bodies. Until recently, it was widely believed that brain Lafora bodies were present exclusively in neurons and thus that Lafora disease pathology derived from their accumulation in this cell population. However, recent evidence indicates that Lafora bodies are also present in astrocytes. To define the role of astrocytic Lafora bodies in Lafora disease pathology, we deleted glycogen synthase specifically from astrocytes in a mouse model of the disease (malinKO). Strikingly, blocking glycogen synthesis in astrocytes—thus impeding Lafora bodies accumulation in this cell type—prevented the increase in neurodegeneration markers, autophagy impairment, and metabolic changes characteristic of the malinKO model. Conversely, mice that overaccumulate glycogen in astrocytes showed an increase in these markers. These results unveil the deleterious consequences of the deregulation of glycogen metabolism in astrocytes and change the perspective that Lafora disease is caused solely by alterations in neurons.

scholarly journals In vivo glutamate clearance defects in a mouse model of Lafora disease

2019 ◽  
Vol 320 ◽  
pp. 112959 ◽  
Author(s):  
C. Muñoz-Ballester ◽  
N. Santana ◽  
E. Perez-Jimenez ◽  
R. Viana ◽  
F. Artigas ◽  
...  
Keyword(s):  
Mouse Model ◽  
Lafora Disease

scholarly journals Pharmacological Interventions to Ameliorate Neuropathological Symptoms in a Mouse Model of Lafora Disease

2015 ◽  
Vol 53 (2) ◽  
pp. 1296-1309 ◽  
Author(s):  
Arnaud Berthier ◽  
Miguel Payá ◽  
Ana M. García-Cabrero ◽  
Maria Inmaculada Ballester ◽  
Miguel Heredia ◽  
...  
Keyword(s):  
Mouse Model ◽  
Lafora Disease ◽  
Pharmacological Interventions

Ppp1r3d deficiency preferentially inhibits neuronal and cardiac Lafora body formation in a mouse model of the fatal epilepsy Lafora disease

2020 ◽  
Author(s):  
Lori Israelian ◽  
Silvia Nitschke ◽  
Peixiang Wang ◽  
Xiaochu Zhao ◽  
Ami M. Perri ◽  
...  
Keyword(s):  
Mouse Model ◽  
Lafora Disease ◽  
Body Formation ◽  
Lafora Body

Transcriptional profiling of a mouse model for Lafora disease reveals dysregulation of genes involved in the expression and modification of proteins

2005 ◽  
Vol 387 (2) ◽  
pp. 62-67 ◽  
Author(s):  
Subramaniam Ganesh ◽  
Naomi Tsurutani ◽  
Kenji Amano ◽  
Shuchi Mittal ◽  
Chiharu Uchikawa ◽  
...  
Keyword(s):  
Mouse Model ◽  
Transcriptional Profiling ◽  
Lafora Disease

scholarly journals Phosphate Incorporation during Glycogen Synthesis and Lafora Disease

2011 ◽  
Vol 13 (3) ◽  
pp. 274-282 ◽  
Author(s):  
Vincent S. Tagliabracci ◽  
Christian Heiss ◽  
Chandra Karthik ◽  
Christopher J. Contreras ◽  
John Glushka ◽  
...  
Keyword(s):  
Glycogen Synthesis ◽  
Lafora Disease ◽  
Phosphate Incorporation

Lafora disease ubiquitin ligase malin promotes proteasomal degradation of neuronatin and regulates glycogen synthesis

2011 ◽  
Vol 44 (1) ◽  
pp. 133-141 ◽  
Author(s):  
Jaiprakash Sharma ◽  
Sudheendra N.R. Rao ◽  
Susarla Krishna Shankar ◽  
Parthasarathy Satishchandra ◽  
Nihar Ranjan Jana
Keyword(s):  
Ubiquitin Ligase ◽  
Glycogen Synthesis ◽  
Proteasomal Degradation ◽  
Lafora Disease

scholarly journals Targeting pathogenic Lafora bodies in Lafora disease using an antibody-enzyme fusion

2019 ◽  
Author(s):  
M. Kathryn Brewer ◽  
Annette Uittenbogaard ◽  
Grant Austin ◽  
John J. McCarthy ◽  
Dyann M. Segvich ◽  
...  
Keyword(s):  
Glycogen Synthesis ◽  
Intractable Epilepsy ◽  
Antibody Fragment ◽  
Glycogen Storage ◽  
Childhood Epilepsy ◽  
Lafora Disease ◽  
Polyglucosan Bodies ◽  
Lafora Bodies ◽  
Enzyme Fusion

AbstractLafora disease (LD) is a fatal childhood epilepsy and a non-classical glycogen storage disorder with no effective therapy or cure. LD is caused by recessive mutations in theEPM2AorEPM2Bgenes that encode the glycogen phosphatase laforin and an E3 ubiquitin ligase malin, respectively. A hallmark of LD is the intracellular accumulation of abnormal and insoluble α-linked polysaccharide deposits known as Lafora bodies (LBs) in several tissues, including most regions of the brain. In mouse models of LD, genetic reduction of glycogen synthesis eliminates LB formation and rescues the neurological phenotype. Since multiple groups have confirmed that neurodegeneration and epilepsy result from LB accumulation, a major focus in the field has shifted toward the development of therapies that reduce glycogen synthesis or target LBs for degradation with the goal of treating LD. Herein, we identify the optimal enzymes for degrading LBs, and we develop a novel therapeutic agent by fusing human pancreatic α-amylase to a cellpenetrating antibody fragment. This antibody-enzyme fusion (VAL-0417) degrades LBsin vitro, shows robust cellular uptake, and significantly reduces the LB loadin vivoinEpm2a-/- mice. VAL-0417 is a promising therapeutic for the treatment of LD and a putative precision therapy for an intractable epilepsy. Antibody-enzyme fusions represent a new class of antibody-based drugs that could be utilized to treat glycogen storage disorders and other diseases.One Sentence SummaryAn antibody-enzyme fusion delivering an amylase degrades the toxic polyglucosan bodies that cause Lafora disease, a fatal childhood epilepsy.

scholarly journals Glycogen metabolism in tissues from a mouse model of Lafora disease

2007 ◽  
Vol 457 (2) ◽  
pp. 264-269 ◽  
Author(s):  
Wei Wang ◽  
Hannes Lohi ◽  
Alexander V. Skurat ◽  
Anna A. DePaoli-Roach ◽  
Berge A. Minassian ◽  
...  
Keyword(s):  
Mouse Model ◽  
Glycogen Metabolism ◽  
Lafora Disease

scholarly journals Differential effects of REV-ERBα/β agonism on cardiac gene expression, metabolism, and contractile function in a mouse model of circadian disruption

2020 ◽  
Vol 318 (6) ◽  
pp. H1487-H1508 ◽  
Author(s):  
Sobuj Mia ◽  
Mariame S. Kane ◽  
Mary N. Latimer ◽  
Cristine J. Reitz ◽  
Ravi Sonkar ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mouse Model ◽  
Mitochondrial Function ◽  
Contractile Function ◽  
Interstitial Fibrosis ◽  
Glycogen Synthesis ◽  
Circadian Clocks ◽  
Cardiac Gene Expression ◽  
Transcriptional Modulators ◽  
Cardiac Gene

Circadian clocks are composed of more than 10 interconnected transcriptional modulators, all of which have the potential to influence the cardiac transcriptome (and ultimately cardiac processes). Previous studies indicate that cardiomyocyte-specific BMAL1 knockout (CBK) mice exhibit a dysfunctional circadian clock (including decreased REV-ERBα/β expression) in the heart, associated with abnormalities in cardiac mitochondrial function, metabolism, signaling, and contractile function. Here we highlight decreased REV-ERBα/β as a mediator of glycogen synthesis, cardiomyocyte size, interstitial fibrosis, and contractile function abnormalities observed in CBK hearts.

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