Summary: New research identifies glucosamine as a major component of brain glycogen and reveals its essential role in protein glycosylation and neurological health.
Source: University of Kentucky
Using advanced imaging and biochemical methods to study brain metabolism, researchers at the University of Kentucky have uncovered where an essential sugar is stored in the brain. Glycogen, long known as the storage form of glucose, also serves as a reservoir for glucosamine, a sugar crucial for protein glycosylation.
The laboratories of Ramon Sun, Ph.D., assistant professor of neuroscience at the Markey Cancer Center, and Matthew Gentry, Ph.D., professor of molecular and cellular biochemistry and director of the Lafora Epilepsy Cure Initiative, found that brain glycogen contains a substantial amount of glucosamine in addition to glucose. Their full study appears in Cell Metabolism.
Outside the cell, glucosamine is commonly known in forms such as glucosamine sulfate or glucosamine hydrochloride, which are widely used as dietary supplements to support joint health. Inside cells, however, glucosamine has a very different and vital role: it provides the building blocks for N-acetylglucosamine-containing sugar chains that are attached to proteins in a process called glycosylation. These sugar modifications are essential for the correct folding, stability, trafficking, and function of many proteins.
The discovery that glucosamine is a significant component of brain glycogen offers new insight into neurological disorders driven by abnormal glycogen-like aggregates known as polyglucosan bodies (PGBs). Lafora disease, a rare inherited form of progressive childhood dementia, is caused by PGB accumulation. This study shows that Lafora PGBs sequester glucosamine, disrupting cellular metabolism and protein glycosylation. Because PGBs also build up with aging and in other neurodegenerative conditions, these findings have wide implications for understanding age-related and disease-related changes in the brain.
Through biochemical analysis of mouse tissues, the team measured the sugar composition of glycogen from muscle, liver, and brain. Muscle glycogen contained only about 1% glucosamine and liver glycogen less than 1%, whereas brain glycogen was composed of approximately 25% glucosamine. “The discovery that brain glycogen is comprised of 25% glucosamine was stunning,” said Dr. Sun.
After this unexpected result, the researchers identified the enzymes that incorporate and remove glucosamine from glycogen. Surprisingly, the same enzymes that synthesize and break down glucose-based glycogen—glycogen synthase and glycogen phosphorylase—also handle glucosamine incorporation and release.
To map the distribution and consequences of altered glycogen chemistry in the brain, the team developed and applied a novel technique: matrix-assisted laser desorption/ionization traveling-wave ion-mobility high-resolution mass spectrometry (MALDI TW IMS). This approach allowed them to quantify and visualize glycogen and its constituent sugars across different brain regions while preserving spatial information. They also used the method to assess changes in N-linked protein glycosylation patterns throughout the brain.
Using MALDI TW IMS, the researchers analyzed healthy mouse brains alongside two mouse models of glycogen storage disorders: a Lafora disease model and a model of glycogen storage disease type III (GSD III). “This new technique lets us measure these sugars with high accuracy and see exactly where they reside in the brain,” said Sun. “For proper brain function, it matters that the right sugars are present in the right places.”
Their experiments showed that when brain glycogen metabolism is impaired, not only do PGBs form—disturbing cellular metabolism—but pools of UDP-N-acetylglucosamine and protein N-glycosylation are also reduced. Importantly, the team demonstrated that clearing PGBs can reverse some of these defects: injecting an antibody–enzyme fusion (VAL-0417) into the brains of Lafora mice degraded PGBs and restored protein glycosylation patterns.
These results establish a direct link between abnormal glycogen storage and defective protein function in the brain. The findings extend beyond Lafora disease: they are relevant to multiple glycogen storage disorders and congenital disorders of glycosylation that produce severe neurological symptoms, including epilepsy and dementia.
“Multiple neurological conditions involve blockages in these metabolic pathways,” Dr. Gentry explained. “We expect these pathways to be important in other brain-centered disorders as well. Brain glycogen contains both glucose and glucosamine, and proper brain metabolism requires balancing both sugars to maintain health.”
The Gentry and Sun laboratories collaborated with several colleagues at the University of Kentucky College of Medicine, including Craig Vander Kooi, Charles Waechter, Lance Johnson, and Christine Brainson. Additional collaborators included Anna A. DePaoli-Roach, Peter J. Roach, and Thomas D. Hurley from the Indiana University School of Medicine, Richard Taylor from the University of Notre Dame, and Richard Drake from the Medical University of South Carolina.
“This transdisciplinary, collaborative research is possible at UK because of strong leadership and institutional support,” Sun noted.
Funding: This research was supported by awards from the National Institutes of Health, including grants from the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Cancer Institute (award numbers cited by the authors). Additional support came from the St. Baldrick’s Career Development Award, a V-Scholar Grant, the Rally Foundation Independent Investigator grant, and the University of Notre Dame Reisenauer Family GSD Research Fund. The content is the responsibility of the authors and does not necessarily represent official NIH views.
About this neuroscience research news
Source: University of Kentucky
Contact: Hillary Smith – University of Kentucky
Image: The image is in the public domain
Original Research: Closed access. “Brain glycogen serves as a critical glucosamine cache required for protein glycosylation” by Ramon Sun et al., Cell Metabolism (DOI cited by the authors)
Abstract
Brain glycogen serves as a critical glucosamine cache required for protein glycosylation
Glycosylation defects are a common feature of many nervous system disorders, but the metabolic origins of these defects are not fully understood. In this study, the authors show that N-linked protein glycosylation in the brain is linked metabolically to glucosamine availability via glycogen breakdown. They demonstrate that glucosamine is an abundant component of brain glycogen and that glycogen functions as a reservoir supplying glucosamine for multiple glycoconjugates.
Using biochemical and structural approaches, primary astrocytes, in vivo stable isotope tracing, and high-resolution mass spectrometry, the authors show that glycogen synthase can incorporate glucosamine into glycogen and that glycogen phosphorylase can release it. In two mouse models of glycogen storage disease, disruption of brain glycogen metabolism led to global reductions in UDP-N-acetylglucosamine pools and in N-linked protein glycosylation. These findings reveal a fundamental biological role for brain glycogen in supporting protein glycosylation with direct implications for multiple central nervous system diseases.