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

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URI: http://nbn-resolving.de/urn:nbn:de:bsz:21-opus-69411
http://hdl.handle.net/10900/43960
Dokumentart: Dissertation
Date: 2013
Language: English
Faculty: 8 Zentrale, interfakultäre und fakultätsübergreifende Einrichtungen
Department: Interdisziplinäre Einrichtungen
Advisor: Schluesener, Hermann (Prof.Dr.)
Day of Oral Examination: 2013-06-26
DDC Classifikation: 500 - Natural sciences and mathematics
Keywords: Histone , Hirntumor
Other Keywords:
Histone acetylation , Epigenetics , Neurodegeneration , Brain Tumor
License: Publishing license excluding print on demand
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Inhaltszusammenfassung:

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.

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.

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