Skeletal Muscle Glycogen Chain Length Correlates with Insolubility in Mouse Models of Polyglucosan-Associated Neurodegenerative Diseases

Mitchell A. Sullivan, Silvia Nitschke, Evan P. Skwara, Peixiang Wang, Xiaochu Zhao, Xiao S. Pan, Erin E. Chown, Travis Wang, Ami M. Perri, Jennifer P.Y. Lee, Francisco Vilaplana, Berge Arakel Minassian, Felix Nitschke

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Lafora disease (LD) and adult polyglucosan body disease (APBD) are glycogen storage diseases characterized by a pathogenic buildup of insoluble glycogen. Mechanisms causing glycogen insolubility are poorly understood. Here, in two mouse models of LD (Epm2a −/− and Epm2b −/− ) and one of APBD (Gbe1 ys/ys ), the separation of soluble and insoluble muscle glycogen is described, enabling separate analysis of each fraction. Total glycogen is increased in LD and APBD mice, which, together with abnormal chain length and molecule size distributions, is largely if not fully attributed to insoluble glycogen. Soluble glycogen consists of molecules with distinct chain length distributions and differential corresponding solubility, providing a mechanistic link between soluble and insoluble glycogen in vivo. Phosphorylation states differ across glycogen fractions and mouse models, demonstrating that hyperphosphorylation is not a basic feature of insoluble glycogen. Lastly, model-specific variances in protein and activity levels of key glycogen synthesis enzymes suggest uninvestigated regulatory mechanisms. EPM2A, EPM2B, or GBE1 deficiency causes insoluble glycogen accumulation and neurodegenerative diseases. Sullivan et al. show that these defects do not impair the construction of WT-like soluble glycogen. Demonstrating varying chain length distributions and correlating precipitation propensity among WT-glycogen molecules, a mechanistic explanation emerges for the structural characteristics of insoluble glycogen.

Original languageEnglish (US)
Pages (from-to)1334-1344.e6
JournalCell Reports
Volume27
Issue number5
DOIs
StatePublished - Apr 30 2019

Fingerprint

Neurodegenerative diseases
Glycogen
Chain length
Neurodegenerative Diseases
Muscle
Skeletal Muscle
Solubility
Lafora Disease
polyglucosan
Molecules
Glycogen Storage Disease
Phosphorylation

Keywords

  • APBD
  • glycogen branching enzyme
  • glycogen chain length distribution
  • glycogen storage disease
  • glycogen synthase
  • Lafora disease
  • laforin
  • malin
  • phosphorylation
  • polyglucosan bodies

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Sullivan, M. A., Nitschke, S., Skwara, E. P., Wang, P., Zhao, X., Pan, X. S., ... Nitschke, F. (2019). Skeletal Muscle Glycogen Chain Length Correlates with Insolubility in Mouse Models of Polyglucosan-Associated Neurodegenerative Diseases. Cell Reports, 27(5), 1334-1344.e6. https://doi.org/10.1016/j.celrep.2019.04.017

Skeletal Muscle Glycogen Chain Length Correlates with Insolubility in Mouse Models of Polyglucosan-Associated Neurodegenerative Diseases. / Sullivan, Mitchell A.; Nitschke, Silvia; Skwara, Evan P.; Wang, Peixiang; Zhao, Xiaochu; Pan, Xiao S.; Chown, Erin E.; Wang, Travis; Perri, Ami M.; Lee, Jennifer P.Y.; Vilaplana, Francisco; Minassian, Berge Arakel; Nitschke, Felix.

In: Cell Reports, Vol. 27, No. 5, 30.04.2019, p. 1334-1344.e6.

Research output: Contribution to journalArticle

Sullivan, MA, Nitschke, S, Skwara, EP, Wang, P, Zhao, X, Pan, XS, Chown, EE, Wang, T, Perri, AM, Lee, JPY, Vilaplana, F, Minassian, BA & Nitschke, F 2019, 'Skeletal Muscle Glycogen Chain Length Correlates with Insolubility in Mouse Models of Polyglucosan-Associated Neurodegenerative Diseases', Cell Reports, vol. 27, no. 5, pp. 1334-1344.e6. https://doi.org/10.1016/j.celrep.2019.04.017
Sullivan, Mitchell A. ; Nitschke, Silvia ; Skwara, Evan P. ; Wang, Peixiang ; Zhao, Xiaochu ; Pan, Xiao S. ; Chown, Erin E. ; Wang, Travis ; Perri, Ami M. ; Lee, Jennifer P.Y. ; Vilaplana, Francisco ; Minassian, Berge Arakel ; Nitschke, Felix. / Skeletal Muscle Glycogen Chain Length Correlates with Insolubility in Mouse Models of Polyglucosan-Associated Neurodegenerative Diseases. In: Cell Reports. 2019 ; Vol. 27, No. 5. pp. 1334-1344.e6.
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