Investigating the role of creatine in oligodendrocyte regeneration during CNS remyelination
Technical Report,15 Jun 2018,14 Jun 2019
GEORGETOWN UNIV WASHINGTON DC WASHINGTON DC United States
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Chronic oligodendrocyte and myelin loss contributes of axonal dysfunction and neurodegeneration in multiple sclerosis MS. Although oligodendrocyte precursor cells OPCs are abundant in the CNS, and are able to regenerate myelin in the early stages of MS, it remains unknown why remyelination fails in the chronic stage of MS. One possibility, which remains to be investigated, is that regenerated oligodendrocytes, despite differentiating from OPCs, fail to survive in MS lesions. It is known that oligodendrocytes appear abnormal and die in MS lesions. Therefore strategies to enhance survival of newly regenerated oligodendrocytes in MS would improve their ability to remyelinate axons. We have found that creatine, a compound involved in cell survival and energetic metabolism, promotes oligodendrocyte survival in culture. When experimental demyelination was performed on mice lacking the expression of Gamt, the enzyme responsible for creatine synthesis, we found that most of the newly regenerated oligodendrocytes died instead of restoring myelin. Remarkably, when creatine was injected directly into the demyelinated tissue, we found that the number of regenerated oligodendrocytes and the extent of myelin labeling in lesions increased significantly. These unexpected and intriguing observations suggest that brain-synthesized creatine plays a crucial role in stimulating remyelination by enhancing regenerated oligodendrocyte survival. Therefore, the goal of this project is to investigate the protective and proregenerative effect of creatine on regenerated oligodendrocyte survival and remyelination in mice. To achieve our goals, we will examine a genetically modified mouse mutant that does not express Gamt in oligodendrocytes, and assess its ability to maintain survival of regenerated oligodendrocytes and myelin after demyelination.
- Anatomy and Physiology