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theses

MAPKs are protein kinases that play crucial roles in regulating cell proliferation, survival and differentiation. In the central nervous system (CNS), p38 MAPK and Erk1/2 play an essential role during development of the oligodendrocyte lineage and are necessary for myelination. However, the effects on mature myelin, particularly under pathological conditions remain unclear. In various neurodegenerative diseases, mature myelin deteriorates, leading to myelin loss and neuronal dysfunction. Several growth factors and cytokines are found to be increased in the demyelinated lesions suggesting that the extracellular stimuli may contribute to the myelin pathology and the subsequent changes in oligodendrocyte phenotypes. In this study, we investigated the effects of growth factor signaling on mature oligodendrocytes and the myelin. Specifically, we investigated the role of Erk1/2 and p38 MAPK activation in triggering oligodendrocyte demyelination. Using an in vitro model for CNS demyelination, we show that growth factors that are found upregulated in CNS lesions, such as FGF-2 promotes myelin breakdown through activation of the Erk1/2 and p38 MAPK pathways. We also show that ectopic activation of either Erk1/2 or p38 MAPK is sufficient to induce demyelination. Our study also indicates that growth factor or MAPK-induced demyelination was not associated with cell death, indicating the possibility of oligodendrocyte de-differentiation. To further investigate this, in chapter three we characterized the phenotype of mature oligodendrocytes following MAPK activation. Ectopic activation of Erk1/2 in mature oligodendrocytes resulted in the down-regulation of myelin proteins and a drastic change in cell morphology. A similar phenotypic change was also observed upon ectopic activation of p38 MAPK. Interestingly, after inducing the phenotypic changes, Erk1/2 activation but not p38 MAPK was sufficient to direct non-proliferating mature oligodendrocytes to re-enter the cell cycle. This result suggests that mature oligodendrocytes may have the ability to regenerate and remyelinate following the myelin loss. These studies also demonstrate that MAPKs are crucial in regulating this process. In chapter four, we investigated whether Erk1/2 mediates oligodendrocyte demyelination induced under pathological conditions. To this end, we used an in vitro model for white matter injury in which diffused axon injury is mimicked by mechanical stretching of the myelinated axons in culture. Our data shows that axonal stretch injury induces oligodendrocyte demyelination independent of axon degeneration and inhibition of Erk1/2 activation has a protective effect on the myelin. Altogether, these results suggest that MAPKs play an essential role in triggering oligodendrocyte demyelination and promoting phenotypic changes that may contribute to the subsequent regenerative process of remyelination.

ETD_5017

Ph.D.

Includes bibliographical references

Includes vita

by Pradeepa Gokina

doi:10.7282/T3V122S3

ETD doctoral

The author owns the copyright to this work.