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

Cell Metab. 2021 Jul 6;33(7):1404-1417.e9. doi: 10.1016/j.cmet.2021.05.003. | PubMed

Ramon C Sun¹, Lyndsay E A Young², Ronald C Bruntz³, Kia H Markussen³, Zhengqiu Zhou³, Lindsey R Conroy⁴, Tara R Hawkinson⁵, Harrison A Clarke⁵, Alexandra E Stanback⁵, Jessica K A Macedo³, Shane Emanuelle³, M Kathryn Brewer⁶, Alberto L Rondon³, Annette Mestas³, William C Sanders³, Krishna K Mahalingan⁷, Buyun Tang⁷, Vimbai M Chikwana⁷, Dyann M Segvich⁷, Christopher J Contreras⁷, Elizabeth J Allenger⁸, Christine F Brainson⁹, Lance A Johnson⁸, Richard E Taylor¹⁰, Dustin D Armstrong¹¹, Robert Shaffer¹², Charles J Waechter³, Craig W Vander Kooi², Anna A DePaoli-Roach⁷, Peter J Roach⁷, Thomas D Hurley⁷, Richard R Drake¹³, Matthew S Gentry¹⁴

1. Department of Neuroscience, University of Kentucky, Lexington, KY, USA; Markey Cancer Center, University of Kentucky, Lexington, KY, USA. Electronic address: ramon.sun@uky.edu.
2. Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA; Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
3. Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA.
4. Department of Neuroscience, University of Kentucky, Lexington, KY, USA; Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
5. Department of Neuroscience, University of Kentucky, Lexington, KY, USA.
6. Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA; Institute for Research in Biomedicine, Barcelona, Spain.
7. Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
8. Department of Physiology, University of Kentucky, Lexington, KY, USA.
9. Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA.
10. Department of Chemistry & Biochemistry and the Warren Center for Drug Discovery, University of Notre Dame, Notre Dame, IN, USA.
11. Parasail LLC, Boston, MA, USA.
12. Enable Therapeutics, Boston, MA, USA.
13. Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, USA.
14. Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA; Markey Cancer Center, University of Kentucky, Lexington, KY, USA. Electronic address: matthew.gentry@uky.edu.

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.

Presented By Ramon Sun | ORCID iD