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Chondroitin Sulfate Glycosaminoglycans Inhibit CNS Myelination with Molecular Specificity
Williams, Jenna
Williams, Jenna
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Abstract
The myelin sheath is formed through oligodendrocyte (OL) cells coiling membrane extensions tightly around axons in the central nervous system (CNS), supporting efficient transfer of electrical signals. Neurodegenerative diseases like multiple sclerosis (MS) lead to the breakdown of the myelin sheath, producing regions of demyelination along axons in the brain and spinal cord. A major obstacle in the treatment of MS and similar diseases is the complexity of the cellular events occurring when the myelin sheath breaks down. Upon demyelination, extracellular chondroitin sulfate proteoglycans (CSPGs) have an increased presence directly around the site of injury in what is termed the glial scar, forming a potential barrier to OLs attempting to regenerate the sheath. CSPGs consist of a protein core with chondroitin sulfate (CS) glycosaminoglycan (GAG) disaccharide chains. It has been shown that specific CS-GAGs inhibit neuron growth. It has also been shown that GAG chains inhibit myelin repair; however, it is unknown if specific CS-GAGs inhibit myelination. To fill this gap, we analyzed OL maturation and myelination using both a cellular model of myelination and an animal model of demyelination. In Chapter 2, we evaluated the effects of five different CS-polysaccharide solutions on OL maturation and we demonstrated that CS-E inhibits OL growth in vitro. In Chapter 3, we applied the cuprizone model of demyelination to a genetic conditional knockout (cKO) model of the carbohydrate sulfotransferase 11 (Chst11) enzymatic pathway in mice. Deletion of Chst11 blocks the biosynthesis of chondroitin sulfates A and E, allowing us to evaluate how remyelination is affected in the absence of CS-A and CS-E. The Chst11 cKO mice were treated with cuprizone to demyelination, and our histological results showed that lack of CS-A and CS-E increased myelination as compared to mice with an intact pathway. Together, our results suggest that CS-E (rather than other CS glycans) has a specific effect on OL maturation and myelination and that targeting CS-E may represent a potential therapeutic strategy for demyelinating diseases.
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2023-01-01
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University of Kansas
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990677_1.pdf
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Keywords
Analytical chemistry, Biology, CS-GAGs, CSPGs, Demyelination, Myelin