Patterns of histone acetylation as targets for novel therapeutic approaches in neurological diseases

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dc.contributor.advisor Schluesener, Hermann (Prof.Dr.) de_DE Ebrahimi, Azadeh de_DE 2013-08-06 de_DE 2014-03-17T11:28:31Z 2013-08-06 de_DE 2014-03-17T11:28:31Z 2013 de_DE
dc.identifier.other 392012154 de_DE
dc.identifier.uri de_DE
dc.description.abstract Neurological diseases, in particular brain tumors and neurodegenerative disorders, cause significant socio-economic burdens on societies. Exploring epigenetic mechanisms in neurological disorders in recent decades has been an emerging tool for describing the pathogenesis of neurological diseases as well as developing new therapeutics. Global histone acetylation is an epigenetic entity whose alternating patterns in various neurological diseases have recently raised special attention concerning its potency for therapeutic development. I investigated patterns of global histone 3 lysine 9 acetylation (H3K9Ac) in various brain tumors and neurodegenerative animal models, such as APPPS1-21 mice model of Alzheimer’s disease (AD), in order to find out the relevance of this target to clinical outcome of the disease and it potency as a target for therapeutic development. I also tried to find out whether natural products with promising neuroprotective effects in preclinical studies affect H3K9Ac status of the nuclei in the studied models. In the present study, it was shown that H3K9Ac levels change variably in different brain diseases including benign and malignant tumors as well as neurodegenerative conditions such as AD. In brain tumors, the global H3K9Ac alterations were correlated to the degree of malignancy and disease aggressive behavior. Regarding neurodegenerative conditions, an aberration of H3K9Ac profile in APPPS1-21 transgenic mice was reported, which was reversed after MS-275 treatment. Likewise, therapeutic effect of valproic acid on experimental autoimmune encephalomyelitis rats was associated with increased H3K9Ac of brain cells. According to the results of in vitro study, typical histone deacetylator enzyme (HDAC) modifiers, either selective or non-selective, did not change H3K9Ac patterns despite revealing antioxidative effects, suggesting alternative mechanisms, such as alteration of acetylation in non-histone proteins or modification of other pathways. Similarly, icariin, a natural substance with SIRT-1 modifying and neuroprotective activity, could not change the H3K9Ac profile of APPPS1-21 mice brain although it revealed anti-amyloid pathology effects. We conclude that H3K9 acetylation is a relevant target in the studied brain diseases and alternative mechanisms might be involved in neuroprotective action of both polyphenol and non-polyphenol HDAC modifiers. en
dc.description.abstract Neurologische Erkrankungen, insbesondere Gehirntumore und neurodegenerative Erkrankungen, verursachen erhebliche sozioökonomische Belastungen für die Gesellschaft. Die Analyse epigenetischer Mechanismen neurologischer Erkrankungen eröffnet neue Methoden zur Untersuchung der Pathogenese und Therapie.. In der vorliegenden Studie wurde gezeigt, dass die histologischen Muster der zellulären H3K9 Azetylierung bei bestimmten Pathologien des Zentralen Nervensystems, wie malignen oder benignen Hirntumoren oder auch neurodegenerativen Prozessen, wie der Alzheimer’schen Krankheit, von klinischer Bedeutung sind.. Wir schließen daraus, dass die H3K9 Azetylierung ein relevantes diagnostisches Kriterium und auch ein Ziel für die Entwicklung therapeutischer Strategien ist. Insbesondere Polyphenole und nicht-polyphenolischen HDAC Modifikatoren haben in dieser Hinsicht großes Potenzial. de_DE
dc.language.iso en de_DE
dc.publisher Universität Tübingen de_DE
dc.rights ubt-podno de_DE
dc.rights.uri de_DE
dc.rights.uri en
dc.subject.classification Histone , Hirntumor de_DE
dc.subject.ddc 500 de_DE
dc.subject.other Histone acetylation , Epigenetics , Neurodegeneration , Brain Tumor en
dc.title Patterns of histone acetylation as targets for novel therapeutic approaches in neurological diseases en
dc.title Muster der Histon-Azetylierung als Ziele für neue therapeutische Ansätze bei neurologischen Erkrankungen de_DE
dc.type PhDThesis de_DE
dcterms.dateAccepted 2013-06-26 de_DE
utue.publikation.fachbereich Interdisziplinäre Einrichtungen de_DE
utue.publikation.fakultaet 8 Zentrale, interfakultäre und fakultätsübergreifende Einrichtungen de_DE
dcterms.DCMIType Text de_DE
utue.publikation.typ doctoralThesis de_DE 6941 de_DE
thesis.grantor Interdisziplinäre Arbeitsgemeinschaften und Einrichtungen de_DE


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