Brain glycogen serves as a critical glucosamine cache required for protein glycosylation

Ramon C. Sun, Lyndsay E.A. Young, Ronald C. Bruntz, Kia H. Markussen, Zhengqiu Zhou, Lindsey R. Conroy, Tara R. Hawkinson, Harrison A. Clarke, Alexandra E. Stanback, Jessica K.A. Macedo, Shane Emanuelle, M. Kathryn Brewer, Alberto L. Rondon, Annette Mestas, William C. Sanders, Krishna K. Mahalingan, Buyun Tang, Vimbai M. Chikwana, Dyann M. Segvich, Christopher J. ContrerasElizabeth J. Allenger, Christine F. Brainson, Lance A. Johnson, Richard E. Taylor, Dustin D. Armstrong, Robert Shaffer, Charles J. Waechter, Craig W. Vander Kooi, Anna A. DePaoli-Roach, Peter J. Roach, Thomas D. Hurley, Richard R. Drake, Matthew S. Gentry

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

Glycosylation defects are a hallmark of many nervous system diseases. However, the molecular and metabolic basis for this pathology is not fully understood. In this study, we found that N-linked protein glycosylation in the brain is metabolically channeled to glucosamine metabolism through glycogenolysis. We discovered that glucosamine is an abundant constituent of brain glycogen, which functions as a glucosamine reservoir for multiple glycoconjugates. We demonstrated the enzymatic incorporation of glucosamine into glycogen by glycogen synthase, and the release by glycogen phosphorylase by biochemical and structural methodologies, in primary astrocytes, and in vivo by isotopic tracing and mass spectrometry. Using two mouse models of glycogen storage diseases, we showed that disruption of brain glycogen metabolism causes global decreases in free pools of UDP-N-acetylglucosamine and N-linked protein glycosylation. These findings revealed fundamental biological roles of brain glycogen in protein glycosylation with direct relevance to multiple human diseases of the central nervous system.

Original languageEnglish
Pages (from-to)1404-1417.e9
JournalCell Metabolism
Volume33
Issue number7
DOIs
StatePublished - Jul 6 2021

Bibliographical note

Publisher Copyright:
© 2021 Elsevier Inc.

Keywords

  • Lafora disease
  • MALDI imaging
  • N-linked glycosylation
  • antibody-enzyme therapy
  • brain metabolism
  • childhood dementia
  • glucosamine
  • glycogen metabolism
  • glycogen storage disease
  • polyglucosan body

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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