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Identifier

000403589

Title

Investigating known and novel protein interactions of the cell adhesion molecule TAG-1 and its implication in the EAE mouse model

Alternative Title

Διερεύνηση γνωστών και νέων πρωτεϊνικών αλληλεπιδράσεων του μορίου κυτταρικής συνάφειας TAG-1 και του ρόλου του στο μοντέλο αυτοάνωσης πειραματικής εγκεφαλομυελίτιδας

Author

Φακουρέλη, Ειρήνη Ν.

Thesis advisor

Καραγωγέως, Δόμνα

Reviewer

Σαββάκη, Μαρία
Καστρίτση, Μαριλένα

Abstract

The main function of the myelin sheath is nerve insulation and subsequent increase of the speed at which electrical signals travel. The axo-glial interactions, which are the interactions between the glial cell and the adjacent axon, segregate the fiber in distinct molecular and functional domains that ensure the rapid propagation of action potentials. These domains are the node of Ranvier, the paranode, the juxtaparanode and the internode. They are characterized by multiprotein complexes between voltage-gated ion channels, cell adhesion molecules, members of the Neurexin family and cytosceletal proteins. TAG-1 (Transient Axonal Glycoprotein-1) a cell adhesion molecule of the Immunoglobulin superfamily, is expressed both by neurons and myelinating glia and is concentrated at the juxtaparanodes of adult central and peripheral nervous system. TAG-1 forms a tripartite complex with the Neurexin protein Caspr2 and the voltage gated potassium channels (VGKCs). More specifically, TAG-1 belongs to the Contactin subfamily which is characterized by four Fibronectin type III (FNIII) repeats and six Ig-like modules. Up to date, it has been shown that TAG-1 interacts in an hοmophilic way with itself in trans through its FNIII repeats. Moreover, it interacts in an heterophilic way in cis with Caspr2 and VGKCs through its Ig-like domains while FNIII repeats do not take place in this interaction. The study of these interactions is of high importance as the complete absence of either TAG-1 or Caspr2 results in disruption of the juxtaparanodal complex and subsequent diffusion of VGKCs towards the internode. In a variety of demyelinating pathologies including Multiple Sclerosis, the molecular architecture of the myelinated fiber is disrupted, leading to axonal degeneration. In the first part of this study, we have analyzed the TAG-1 subdomains implicated in its interaction with Caspr2 and we investigated the role of a released form of TAG-1 in this interaction. Our results were contradictory with what was previously shown as almost all the TAG-1 subdomains, FNIII repeats included, could interact with Caspr2. Furthermore, we identified Semaphorin6A and Neurofascin isoforms 140 and 155 as novel interactors of TAG-1. In the second part of this study, in an effort to further study the role of TAG-1 in myelination, we focused on the role of TAG-1 in the demyelination murine model of Experimental Autoimmune Encephalomyelitis (EAE). TAG-1 absence resulted in a delay in the development of neurological symptoms, linked to a reduced recruitment of regulatory T cells in the spinal cord.

Language

English

Subject

Axo-glial interactions

Cell adhesion molecules

Demyelination

Experimental autoimmune encephalomyelitis

Nodes of Ranvier

TAG-1/CONTACTIN-2

Αξονο-γλοιακές αλληλεπιδράσεις

Απομυελίνωση

Αυτοάνωση πειραματική εγκεφαλομυελίτιδα