Glycogen synthase GYS1 overactivation contributes to glycogen insolubility and malto-oligoglucan-associated neurodegenerative disease

Silvia Nitschke; Alina P. Montalbano; Megan E. Whiting; Brandon H. Smith; Neije Mukherjee-Roy; Charlotte R. Marchioni; Mitchell A. Sullivan; Xiaochu Zhao; Peixiang Wang; Howard Mount; Mayank Verma; Berge A. Minassian; Felix Nitschke

doi:10.1038/s44318-024-00339-3

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Glycogen synthase GYS1 overactivation contributes to glycogen insolubility and malto-oligoglucan-associated neurodegenerative disease

Journal article

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Peer reviewed

Glycogen synthase GYS1 overactivation contributes to glycogen insolubility and malto-oligoglucan-associated neurodegenerative disease

Silvia Nitschke, Alina P. Montalbano, Megan E. Whiting, Brandon H. Smith, Neije Mukherjee-Roy, Charlotte R. Marchioni, Mitchell A. Sullivan, Xiaochu Zhao, Peixiang Wang, Howard Mount, …

The EMBO Journal, Vol.44, pp.1379-1413

2025

DOI: https://doi.org/10.1038/s44318-024-00339-3

PMCID: PMC11876434

PMID: 39806098

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Abstract

Lafora disease

adult polyglucosan body disease

neuroinflammation

biomarkers

glycogen

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 Center
Alina P. Montalbano - The University of Texas Southwestern Medical Center
Megan E. Whiting - The University of Texas Southwestern Medical Center
Brandon H. Smith - The University of Texas Southwestern Medical Center
Neije Mukherjee-Roy - The University of Texas Southwestern Medical Center
Charlotte R. Marchioni - The University of Texas Southwestern Medical Center
Mitchell A. Sullivan - University of the Sunshine Coast, Queensland, School of Health - Biomedicine
Xiaochu Zhao - Hospital for Sick Children
Peixiang Wang - Hospital for Sick Children
Howard Mount - University of Toronto
Mayank Verma - The University of Texas Southwestern Medical Center
Berge A. Minassian (Corresponding Author) - The University of Texas Southwestern Medical Center
Felix 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
PMID: 39806098; PMC11876434
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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Collaboration types: Domestic collaboration; International collaboration
Web Of Science research areas: Biochemistry & Molecular Biology; Cell Biology

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