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Journal article
Glycogen synthase GYS1 overactivation contributes to glycogen insolubility and malto-oligoglucan-associated neurodegenerative disease
The EMBO Journal, Vol.44, pp.1379-1413
2025
PMID: 39806098
Abstract
Polyglucosans are glycogen molecules with overlong chains, which are hyperphosphorylated in the neurodegenerative Lafora disease (LD). Brain polyglucosan bodies (PBs) cause fatal neurodegenerative diseases including Lafora disease and adult polyglucosan body disease (ABPD), for which treatments, biomarkers, and good understanding of their pathogenesis are currently missing. Mutations in the genes for the phosphatase laforin or the E3 ubiquitin ligase malin can cause LD. By depleting PTG, an activator of the glycogen chain-elongating enzyme glycogen synthase (GYS1), in laforin- and malin-deficient LD mice, we show that abnormal glycogen chain lengths and not hyperphosphorylation underlie polyglucosan formation, and that polyglucosan bodies induce neuroinflammation. We provide evidence indicating that a small pool of overactive GYS1 contributes to glycogen insolubility in LD and APBD. In contrast to previous findings, metabolomics experiments using in situ-fixed brains reveal only modest metabolic changes in laforin-deficient mice. These changes are not replicated in malin-deficient or APBD mice, and are not normalized in rescued LD mice. Finally, we identify a pool of metabolically volatile malto-oligoglucans as a polyglucosan body- and neuroinflammation-associated brain energy source, and promising candidate biomarkers for LD and APBD, including malto-oligoglucans and the neurodegeneration marker CHI3L1/YKL40.
Details
- Title
- Glycogen synthase GYS1 overactivation contributes to glycogen insolubility and malto-oligoglucan-associated neurodegenerative disease
- Authors
- Silvia Nitschke - The University of Texas Southwestern Medical CenterAlina P. Montalbano - The University of Texas Southwestern Medical CenterMegan E. Whiting - The University of Texas Southwestern Medical CenterBrandon H. Smith - The University of Texas Southwestern Medical CenterNeije Mukherjee-Roy - The University of Texas Southwestern Medical CenterCharlotte R. Marchioni - The University of Texas Southwestern Medical CenterMitchell A. Sullivan - University of the Sunshine Coast, Queensland, School of Health - BiomedicineXiaochu Zhao - Hospital for Sick ChildrenPeixiang Wang - Hospital for Sick ChildrenHoward Mount - University of TorontoMayank Verma - The University of Texas Southwestern Medical CenterBerge A. Minassian (Corresponding Author) - The University of Texas Southwestern Medical CenterFelix Nitschke (Corresponding Author) - The University of Texas Southwestern Medical Center
- Publication details
- The EMBO Journal, Vol.44, pp.1379-1413
- Publisher
- EMBO Press
- Date published
- 2025
- DOI
- 10.1038/s44318-024-00339-3
- ISSN
- 1460-2075; 0261-4189
- PMID
- 39806098
- Copyright note
- © 2025 The Author(s). Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material.
- Grant note
- HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS): P01NS097197, R01NS128437; Chan Zuckerberg Initiative (CZI): 2022-316703
- Organisation Unit
- School of Health - Biomedicine
- Language
- English
- Record Identifier
- 991103723102621
- Output Type
- Journal article
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