ArticleThe Journal of biological chemistry
An inducible glycogen synthase-1 knockout halts but does not reverse Lafora disease progression in mice.
Article in The Journal of biological chemistry. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 31 citations in OpenAlex.
- Large-Scale Protein Production and Activity Assay Protocols for Human Glycogen Synthase-Glycogenin Complex.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Clinicopathologic Dissociation: Robust Lafora Body Accumulation in Malin KO Mice Without Observable Changes in Home-Cage Behavior.The Journal of comparative neurology · 2024Article
- Implications of aCurrent issues in molecular biology · 2024Article
- Lafora Disease: A Case Report and Evolving Treatment Advancements.Brain sciences · 2023Article
- Role of Astrocytes in the Pathophysiology of Lafora Disease and Other Glycogen Storage Disorders.Cells · 2023Review
- Laforin targets malin to glycogen in Lafora progressive myoclonus epilepsy.Disease models & mechanisms · 2023Article
- Early Treatment with Metformin Improves Neurological Outcomes in Lafora Disease.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2023Article
- Glial Contributions to Lafora Disease: A Systematic Review.Biomedicines · 2022Review
- In situ mass spectrometry imaging reveals heterogeneous glycogen stores in human normal and cancerous tissues.EMBO molecular medicine · 2022Article
- Glycogen synthase downregulation rescues the amylopectinosis of murine RBCK1 deficiency.Brain : a journal of neurology · 2022Article
- Lafora disease: Current biology and therapeutic approaches.Revue neurologique · 2022Review
- Lack of p62 Impairs Glycogen Aggregation and Exacerbates Pathology in a Mouse Model of Myoclonic Epilepsy of Lafora.Molecular neurobiology · 2022Article
- Malin restoration as proof of concept for gene therapy for Lafora disease.Brain communications · 2022Article
- Gys1 antisense therapy rescues neuropathological bases of murine Lafora disease.Brain : a journal of neurology · 2021Article
- LUBAC: a new player in polyglucosan body disease.Biochemical Society transactions · 2021Review
- Alleviation of a polyglucosan storage disorder by enhancement of autophagic glycogen catabolism.EMBO molecular medicine · 2021Article
- The 6th International Lafora Epilepsy Workshop: Advances in the search for a cure.Epilepsy & behavior : E&B · 2021Review
- Targeting Gys1 with AAV-SaCas9 Decreases Pathogenic Polyglucosan Bodies and Neuroinflammation in Adult Polyglucosan Body and Lafora Disease Mouse Models.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2021Article
- miR-140-5p Aggravates Insulin Resistance via Directly Targeting GYS1 and PPP1CC in Insulin-Resistant HepG2 Cells.Diabetes, metabolic syndrome and obesity : targets and therapy · 2021Article
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Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
Abstract
Malstructured glycogen accumulates over time in Lafora disease (LD) and precipitates into Lafora bodies (LBs), leading to neurodegeneration and intractable fatal epilepsy. Constitutive reduction of glycogen synthase-1 (GYS1) activity prevents murine LD, but the effect of GYS1 reduction later in disease course is unknown. Our goal was to knock out Gys1 in laforin (Epm2a)-deficient LD mice after disease onset to determine whether LD can be halted in midcourse, or even reversed. We generated Epm2a-deficient LD mice with tamoxifen-inducible Cre-mediated Gys1 knockout. Tamoxifen was administered at 4 months and disease progression assessed at 12 months. We verified successful knockout at mRNA and protein levels using droplet digital PCR and Western blots. Glycogen determination and periodic acid-Schiff-diastase staining were used to analyze glycogen and LB accumulation. Immunohistochemistry using astrocytic (glial fibrillary acidic protein) and microglial (ionized calcium-binding adapter molecule 1) markers was performed to investigate neuroinflammation. In the disease-relevant organ, the brain, Gys1 mRNA levels were reduced by 85% and GYS1 protein depleted. Glycogen accumulation was halted at the 4-month level, while LB formation and neuroinflammation were significantly, though incompletely, prevented. Skeletal muscle analysis confirmed that Gys1 knockout inhibits glycogen and LB accumulation. However, tamoxifen-independent Cre recombination precluded determination of disease halting or reversal in this tissue. Our study shows that Gys1 knockdown is a powerful means to prevent LD progression, but this approach did not reduce brain glycogen or LBs to levels below those at the time of intervention. These data suggest that endogenous mechanisms to clear brain LBs are absent or, possibly, compromised in laforin-deficient murine LD.
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