Investigating the Role of Creatine in Oligodendrocyte Regeneration During CNS Remyelination
Abstract
Chronic oligodendrocyte and myelin loss contributes of axonal dysfunction and neurodegeneration in multiple sclerosis (MS). Although oligodendrocyte precursor cells (OPCs) are abundant in the central nervous system, 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. We will also determine whether altered creatine levels and reduced regenerated oligodendrocyte survival occurs in aged mice, since advanced age has been suggested as a contributor to remyelination failure and disease progression in MS. Moreover, we will determine whether oral administration of creatine and cyclocreatine, a brain permeable creatine analog, could have therapeutic benefit in promoting remyelination. Finally, we will establish a comprehensive profile of genes associated with creatine activity in regenerated oligodendrocytes for the identification of potential novel drug targets in oligodendrocyte protection and remyelination. Results from this study will demonstrate whether creatine synthesis in the brain is required for successful remyelination and whether oral administration of creatine/cyclocreatine can enhance remyelination. If oral creatine/cyclocreatine administration can promote oligodendrocyte survival and remyelination, then our results would be highly translatable to MS patients at any stage of the disease. Creatine and cylocreatine are readily obtainable and do not appear to exhibit significant side effects. Therefore, this study could lead to the use of creatine/cyclocreatine as a therapeutic compound to protect regenerated oligodendrocytes and improve remyelination in MS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710268
Entities
People
- Jeffrey K Huang
Organizations
- Georgetown University
- United States Army