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Ann Clin Transl Neurol - 2020 - Chown - GYS1 or PPP1R3C deficiency rescues murine adult polyglucosan body disease4.60 MB
Published VersionCC BY-NC-ND V4.0, Open Access
Journal article
GYS1 or PPP1R3C deficiency rescues murine adult polyglucosan body disease
Annals of Clinical and Translational Neurology, Vol.7(11), pp.2186-2198
2020
PMID: 33034425
Abstract
Adult polyglucosan body disease (APBD) is an adult-onset neurological variant of glycogen storage disease type IV. APBD is caused by recessive mutations in the glycogen branching enzyme gene, and the consequent accumulation of poorly branched glycogen aggregates called polyglucosan bodies in the nervous system. There are presently no treatments for APBD. Here, we test whether downregulation of glycogen synthesis is therapeutic in a mouse model of the disease.
We characterized the effects of knocking out two pro-glycogenic proteins in an APBD mouse model. APBD mice were crossed with mice deficient in glycogen synthase (GYS1), or mice deficient in protein phosphatase 1 regulatory subunit 3C (PPP1R3C), a protein involved in the activation of GYS1. Phenotypic and histological parameters were analyzed and glycogen was quantified.
APBD mice deficient in GYS1 or PPP1R3C demonstrated improvements in life span, morphology, and behavioral assays of neuromuscular function. Histological analysis revealed a reduction in polyglucosan body accumulation and of astro- and micro-gliosis in the brains of GYS1- and PPP1R3C-deficient APBD mice. Brain glycogen quantification confirmed the reduction in abnormal glycogen accumulation. Analysis of skeletal muscle, heart, and liver found that GYS1 deficiency reduced polyglucosan body accumulation in all three tissues and PPP1R3C knockout reduced skeletal muscle polyglucosan bodies.
GYS1 and PPP1R3C are effective therapeutic targets in the APBD mouse model. These findings represent a critical step toward the development of a treatment for APBD and potentially other glycogen storage disease type IV patients.
Details
- Title
- GYS1 or PPP1R3C deficiency rescues murine adult polyglucosan body disease
- Authors
- Erin E Chown - Hospital for Sick ChildrenPeixiang Wang - Hospital for Sick ChildrenXiaochu Zhao - Hospital for Sick ChildrenJustin J Crowder - Ball State UniversityJordan W Strober - Ball State UniversityMitchell A Sullivan - Hospital for Sick ChildrenYunlin Xue - Hospital for Sick ChildrenCody S Bennett - Ball State UniversityAmi M Perri - Hospital for Sick ChildrenBret M Evers - The University of Texas Southwestern Medical CenterPeter J Roach - Indiana University School of MedicineAnna A Depaoli-Roach - Indiana University School of MedicineH Orhan Akman - Columbia UniversityBartholomew A Pederson - Ball State UniversityBerge A Minassian (Corresponding Author) - Hospital for Sick Children
- Publication details
- Annals of Clinical and Translational Neurology, Vol.7(11), pp.2186-2198
- Publisher
- John Wiley & Sons Ltd.
- Date published
- 2020
- DOI
- 10.1002/acn3.51211
- ISSN
- 2328-9503
- PMID
- 33034425
- Copyright note
- © 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
- Organisation Unit
- School of Health - Biomedicine
- Language
- English
- Record Identifier
- 991035095102621
- Output Type
- Journal article
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