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

Autor:	Sun RC; Department of Neuroscience, University of Kentucky, Lexington, KY, USA; Markey Cancer Center, University of Kentucky, Lexington, KY, USA. Electronic address: ramon.sun@uky.edu., Young LEA; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA; Markey Cancer Center, University of Kentucky, Lexington, KY, USA., Bruntz RC; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA., Markussen KH; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA., Zhou Z; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA., Conroy LR; Department of Neuroscience, University of Kentucky, Lexington, KY, USA; Markey Cancer Center, University of Kentucky, Lexington, KY, USA., Hawkinson TR; Department of Neuroscience, University of Kentucky, Lexington, KY, USA., Clarke HA; Department of Neuroscience, University of Kentucky, Lexington, KY, USA., Stanback AE; Department of Neuroscience, University of Kentucky, Lexington, KY, USA., Macedo JKA; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA., Emanuelle S; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA., Brewer MK; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA; Institute for Research in Biomedicine, Barcelona, Spain., Rondon AL; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA., Mestas A; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA., Sanders WC; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA., Mahalingan KK; Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA., Tang B; Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA., Chikwana VM; Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA., Segvich DM; Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA., Contreras CJ; Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA., Allenger EJ; Department of Physiology, University of Kentucky, Lexington, KY, USA., Brainson CF; Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA., Johnson LA; Department of Physiology, University of Kentucky, Lexington, KY, USA., Taylor RE; Department of Chemistry & Biochemistry and the Warren Center for Drug Discovery, University of Notre Dame, Notre Dame, IN, USA., Armstrong DD; Parasail LLC, Boston, MA, USA., Shaffer R; Enable Therapeutics, Boston, MA, USA., Waechter CJ; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA., Vander Kooi CW; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA; Markey Cancer Center, University of Kentucky, Lexington, KY, USA., DePaoli-Roach AA; Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA., Roach PJ; Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA., Hurley TD; Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA., Drake RR; Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, USA., Gentry MS; 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.
Jazyk:	angličtina
Zdroj:	Cell metabolism [Cell Metab] 2021 Jul 06; Vol. 33 (7), pp. 1404-1417.e9. Date of Electronic Publication: 2021 May 26.
DOI:	10.1016/j.cmet.2021.05.003
Abstrakt:	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. Competing Interests: Declaration of interests M.S.G. is a consultant for Maze Therapeutics, Enable Therapeutics, Glut1-Deficiency Syndrome Foundation, and Chelsea's Hope. M.S.G., R.C.S., C.W.V.K., and R.C.B. are founders of Atterogen, LLC. (Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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