| Abstract |
In the first part of this doctoral thesis we investigated the activity of BNN27, a member of a chemical library of C17-spiroepoxy derivatives of the neurosteroid DHEA. BNN27 has been shown to regulate neuronal survival through its selective interaction with NGF receptors (TrkA and p75NTR), but its role on glial populations has not been studied. Here we report that BNN27 provides trophic action (i.e. rescue from apoptosis), in a TrkA-dependent manner, to mature oligodendrocytes when they are challenged with the cuprizone toxin in culture. BNN27 treatment also increases oligodendrocyte maturation and diminishes microglia activation in vitro. The effect of BNN27 in the cuprizone mouse model of demyelination in vivo has also been investigated. In this model, that does not directly involve the adaptive immune system, BNN27 is able to protect from demyelination without affecting the remyelinating process. BNN27 preserves mature oligodendrocyte during demyelination, while reducing microgliosis and astrogliosis. Our findings suggest that BNN27 may serve as a lead molecule to develop neurotrophin-like, blood brain barrier (BBB)-permeable protective agents of oligodendrocyte populations and myelin, with potential applications in the treatment of demyelinating disorders.
In the second part of the research, we focused on the identification of novel partners of TAG-1. TAG-1 is a GPI-anchored protein interacting with the transmembrane protein Caspr2 and the voltage-gated potassium channels expressed on the axon, forming a cluster in the juxtaparanodal area. Four putative TAG-1 interactors (MAP1B, MAP2, Reelin and TenascinR) were selected. These proteins were identified using a new computational tool called UniReD, which is able to predict new protein-protein interactions not yet documented in the literature. We describe that TAG-1 interacts (directly or indirectly) with MAP1B and Reelin, while no interaction was visible with MAP2 and TenascinR. MAP1B holds an important role in the regulation of microtubule dynamics, and microtubule-actin interactions, and it mediates growth cone as well as neuronal migration. Reelin is a large secreted extracellular matrix glycoprotein that regulates processes of neuronal migration and positioning in the developing brain by controlling cell-cell interactions. These novel identified interactions may not be associated with the juxtaparanodal partners of TAG-1, but they may be important for its developmental functions.
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The role of the novel synthetic microneurotrophin BNN27 in glial cells in health and demyelination
