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"Enhancing the regenerative potential of the CNS: the complex functions of TSC and mTOR in oligodendrocyte remyelination"

by
Lauren E. McLane
Neuroscience Program
B.S. 2010, Allegheny College


Thesis Advisor: Teresa Wood, PhD
Professor
Department of Pharmacology, Physiology and Neuroscience

Wednesday, October 26, 2016
11:00 A.M., Cancer Center, G-1196


Abstract

Myelin is critical for fast and synchronous signal conduction throughout the nervous system and for providing metabolic and trophic support to axons. In demyelinating disorders such as Multiple Sclerosis, myelin is damaged and lost, resulting in disability. Encouragingly, the nervous system is capable of spontaneous, endogenous remyelination. Within the central nervous system (CNS), oligodendrocytes are the glial cells that produce myelin, extending processes to contact and wrap axon segments. Oligodendrocyte progenitor cells (OPCs) are present throughout the adult CNS and can respond to a demyelinating event by migrating into the lesion, differentiating into mature oligodendrocytes and remyelinating the denuded axons. Unfortunately, this regenerative process often fails. Intriguingly, many chronically demyelinated lesions are not devoid of oligodendroglia but have OPCs or pre-myelinating oligodendrocytes within their borders. It is consequently of great interest to elucidate mechanisms by which we can enhance endogenous remyelination by promoting the full maturation of oligodendroglia.
The mTOR signaling pathway has emerged as a key regulator of developmental oligodendrocyte differentiation and myelination. Loss of mTOR from developing OPCs results in fewer mature oligodendrocytes and hypomyelination. Surprisingly, loss of tuberous sclerosis complex (TSC), an upstream inhibitor of mTOR, also results in developmental hypomyelination. Despite its known importance in developmental myelination, mTOR and TSC signaling has not been extensively studied in remyelination.
Here, we utilize a mouse model of focal demyelination to study the function of the TSC/mTOR signaling pathway in remyelination. We provide evidence that genetic deletion of Tsc1 has opposite effects on remyelination depending on the stage in the oligodendrocyte lineage from which it is deleted. Tsc1 deletion from OPCs is beneficial to remyelination, increasing both the area of remyelination and the thickness of myelin on remyelinated axons without affecting OPC differentiation. Conversely, Tsc1 deletion from differentiated oligodendrocytes is detrimental, reducing remyelination.
We further show that deletion of mTOR from the oligodendrocyte lineage in either OPCs or differentiated oligodendrocytes is not detrimental to OPC differentiation or myelination during remyelination. Taken together, these data reveal complex roles for TSC and mTOR in remyelination and highlight differences in the regulation of developmental myelination and remyelination.


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