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dc.contributor.advisor Nave, Klaus-Armin Prof. Dr. de
dc.contributor.author Kasapoglu, Burcu de
dc.date.accessioned 2013-01-25T10:11:19Z de
dc.date.available 2013-01-30T23:51:00Z de
dc.date.issued 2013-01-25 de
dc.identifier.uri http://hdl.handle.net/11858/00-1735-0000-000D-F1B2-4 de
dc.language.iso eng de
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/3.0/
dc.subject.ddc 570 de
dc.subject.ddc 150 de
dc.title Role of myelin-associated NAD+- dependent deacetylase Sirtuin 2 in modifying axonal degeneration de
dc.type doctoralThesis de
dc.contributor.referee Brose, Nils Prof. Dr. de
dc.date.examination 2012-02-01 de
dc.description.abstracteng In the central nervous system (CNS), oligodendrocytes (OLs) ensheath axons with lipid-rich myelin membranes that provide an electrical insulation and are essential for fast nerve impulse transmission. However, myelination is not the only function of OLs, which is important for neurons. The axo-glial interaction is vital for the long-term survival of the axons, independently from myelination. The novel role of OLs in supporting axonal integrity was best exemplified by the findings on mutant mice with the genetic deletion of two structural proteins of the CNS myelin, namely proteolipid protein (PLP) and 2’-3’-cyclic nucleotide phosphodiesterase (CNP1). Lack of these proteins led to an axonopathy in the CNS, despite the absence of major myelin abnormalities. Gel-based proteome analysis performed to explore possible secondary molecular alterations in Plpnull myelin revealed that Sirtuin 2 (SIRT2) was the only protein, other than PLP and its splice isoform DM20, to be virtually absent. These findings suggested that the axonal pathology observed in Plpnull mice may be at least partially due to the lack of SIRT2. SIRT2 is one of the mammalian orthologs of the silent information regulator 2 (Sir2) protein, which is an nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase and is involved in many cellular mechanisms in yeast and worms. SIRT2 has a cytoplasmic distribution, to colocalize with microtubule network and to deacetylate α-tubulin at the lysine-40 residue. SIRT2 is highly expressed in the brain, specifically in oligodendrocytes at early stages of myelination and is incorporated into myelin in presence of PLP/DM20, being localized at the inner and outer loops and the paranodes of the CNS myelin.  To identify the role of SIRT2 in the axon protection, we analyzed mice lacking Sirt2 expression. Surprisingly, we found that SIRT2 is dispensable for myelin formation and maintenance, as axons of all calibers in both the central and peripheral nervous system were normally myelinated in the Sirt2null mice. In addition, these mice showed no apparent CNS axonopathy suggesting that SIRT2 may not be the only key player of the yet unexplained axonoprotective function of PLP.  To test the hypothesis that SIRT2 serves as an NAD+-dependent regulator of glial neuroprotection, we did not only use pharmacological approaches to induce axonal stress, but we also generated double mutant mice expressing neuronal and glial disease genes. For example, we found that the axonal degeneration caused by the lack of Cnp1 was dramatically enhanced by the additional absence of Sirt2. As a result, the Sirt2*Cnp1 double null mutant mice displayed increased inflammation, and a significantly reduced lifespan. These findings support the hypothesis that SIRT2 is a myelin-associated sensor for axonal stress that is essential for long-term axonal survival. de
dc.contributor.coReferee Fischer, André Prof. Dr. de
dc.subject.eng Oligodendrocytes, myelin, axo-glia interactions, Sirtuins, SIRT2, acetylation de
dc.subject.eng myelin de
dc.subject.eng axo-glia interactions de
dc.subject.eng Sirtuins de
dc.subject.eng SIRT2 de
dc.subject.eng acetylation de
dc.identifier.urn urn:nbn:de:gbv:7-11858/00-1735-0000-000D-F1B2-4-4 de
dc.affiliation.institute Biologische Fakultät inkl. Psychologie de
dc.subject.gokfull Biologie (PPN619462639) de
dc.identifier.ppn 737346299 de

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