Defense Date

2008

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Biochemistry

First Advisor

Carmen Sato-Bigbee

Abstract

Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) characterized by demyelination and loss of oligodendrocytes (OLGs), the CNS myelin-producing cells. Thus, understanding the mechanisms that control OLG development can provide valuable knowledge regarding remyelination therapies for MS. This disease is thought to result from an autoimmune attack towards myelin. FTY720, an immunomodulator under evaluation for MS treatment is a sphingosine-1-phosphate (S1P) analog. We found before that S1P plays a crucial role in the NT-3-mediated survival of OLGs, an observation that led us to investigate whether FTY720 could have any effect on these cells. Our studies demonstrate that FTY720 indeed has a direct effect on OLG progenitors, protecting them from apoptotic death through a mechanism involving ERK1/2 and Akt activation. However, another key finding of our study was that this drug arrested OLG differentiation, an effect counteracted by NT-3 which not only enhanced the survival of OLG progenitors but also stimulated their maturation. Furthermore, NT-3 induced an increase in myelin basic protein (MBP) levels in the absence of effects on MBP gene promoter activation or mRNA expression. These observations suggested that NT-3 up-regulated MBP levels by a posttranscriptional mechanism raising the question of whether this neurotrophin could have a more general positive effect on the expression of other OLG proteins. In agreement with this idea, we found that NT-3 also induced the expression of the myelin proteins MAG and MOG. Additionally, [35S]-Methionine labeling indicated a 50% increase in de novo protein synthesis following only a 15 min exposure to NT-3. Such a rapid increase in protein synthesis reinforced the idea that NT-3 plays a crucial role regulating protein expression by posttranscriptional mechanisms. In support of this possibility, we found that NT-3 stimulated the phosphorylation of the initiation factor eIF4E and its inhibitory partner 4EBP1, both essential players in mediating cap-dependent protein synthesis. This stimulation involved the activation of ERK1/2 and PI3K/mTOR mediated signaling pathways. To our knowledge, this is the first study on the regulation of translation initiation in OLGs and the first report describing the potential role of NT-3 as an activator of initiation.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

December 2008

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