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A novel role for the E3 ubiquitin ligase FBXO7 in axon-myelin interaction

dc.contributor.advisorStegmüller, Judith Dr.
dc.contributor.authorJoseph, Sabitha Lis
dc.date.accessioned2018-06-06T10:14:10Z
dc.date.available2018-06-06T10:14:10Z
dc.date.issued2018-06-06
dc.identifier.urihttp://hdl.handle.net/11858/00-1735-0000-002E-E414-8
dc.identifier.urihttp://dx.doi.org/10.53846/goediss-6873
dc.language.isoengde
dc.relation.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.ddc570de
dc.titleA novel role for the E3 ubiquitin ligase FBXO7 in axon-myelin interactionde
dc.typedoctoralThesisde
dc.contributor.refereeStegmüller, Judith Dr.
dc.contributor.refereeBrück, Wolfgang Prof. Dr.
dc.date.examination2017-09-29
dc.description.abstractengThe regulated turnover of proteins is an essential aspect of every cell. Cells must be able to respond to environmental changes or undergo different developmental stages, while still maintaining a balanced protein homeostasis. The ubiquitin-proteasome system (UPS) is a major intracellular regulator of the protein homeostasis and is responsible for protein degradation and quality control. Dysfunctions of the UPS have been linked to various neurodegenerative diseases and opened up a new perspective on the disease-causing mechanism in these disorders. The E3-uniquitin ligase FBXO7 is part of the UPS and is expressed throughout the brain, predominantly in the cortex, hippocampus and substantia nigra, as well as in the white matter of the cerebellum and corpus callosum. Mutations of the Fbxo7 gene (PARK15) are known to cause an early-onset form of Parkinsonism with a broad spectrum of symptoms, which are collectively referred to as Parkinsonian-Pyramidal syndrome. So far, the role of FBXO7 in the nervous system is not fully understood and while recent studies focused on the function of FBXO7 in neurons, its importance in myelinating cells has not been investigated. Although myelinating cells are as equally important to the function of the nervous system as neurons, little is known about the relevance of the UPS in myelinating cells. In my project, I investigated the importance of FBXO7 for myelinating cells and its impact on the axon-myelin interaction. Therefore, we generated the Cnp1Cre/+;Fbxo7fl/fl mouse line, in which FBXO7 was deleted from myelinating cells. The phenotype of Cnp1Cre/+;Fbxo7fl/fl mice displayed severe motor deficit and premature death. Interestingly, I showed that deletion of Fbxo7 did not induce significant changes in myelination, however severely affected the integrity of axons. Moreover, deletion of Fbxo7 from Schwann cells affected the survival of axons in the PNS to a greater extent, than the integrity of CNS axons, when deleted from oligodendrocytes. In order to elucidate the post-developmental contribution of FBXO7 to the maintenance of the axon-glia interaction, I further generated the Tamoxifen–inducible Plp1CreERT2/+;Fbxo7fl/fl mouse line, in which FBXO7 was deleted from myelinating cells once myelination was completed. I found FBXO7 to be less crucial, however still relevant for the function of myelinating cells regarding axonal support, once myelination was completed. Concluding from my results, I demonstrate the vital importance of FBXO7 for myelinating cells, particularly during development. Furthermore, I showed that FBXO7 is essential for the maintenance of the axon-myelin interaction, especially in the PNS.de
dc.contributor.coRefereeNave, Klaus-Armin Prof. Dr.
dc.subject.engFBXO7de
dc.subject.engMyelinde
dc.subject.engaxon-myelin interactionde
dc.subject.engPARK15de
dc.subject.engUPSde
dc.subject.engOligodendrocytesde
dc.subject.engSchwann cellsde
dc.subject.engaxonal deathde
dc.identifier.urnurn:nbn:de:gbv:7-11858/00-1735-0000-002E-E414-8-6
dc.affiliation.instituteGöttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB)de
dc.subject.gokfullBiologie (PPN619462639)de
dc.identifier.ppn1024081117


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