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dc.contributor.advisor Zerr, Inga Prof. Dr.
dc.contributor.author Thüne, Katrin
dc.date.accessioned 2019-10-09T09:46:06Z
dc.date.available 2019-10-09T09:46:06Z
dc.date.issued 2019-10-09
dc.identifier.uri http://hdl.handle.net/21.11130/00-1735-0000-0005-126B-F
dc.language.iso eng de
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.ddc 610
dc.title Regional-dependent, comprehensive characterization of miRNA signatures in sporadic Creutzfeldt-Jakob Disease and early Alzheimer’s Disease-type neuropathology de
dc.type doctoralThesis de
dc.contributor.referee Simons, Mikael Prof. Dr.
dc.date.examination 2018-10-11
dc.description.abstracteng The pathogenic mechanisms and the origins of neurodegenerative diseases remain unclear on molecular level. Increasing evidences postulate alterations in miRNA signatures as critical factor in pathogenesis, progression and prognosis of neurodegenerative disorders. miRNAs are a class of small non-coding RNAs shaping gene expression post-transcriptionally. As a regulator of cellular functions and homeostasis, miRNAs maintain brain cell integrity and their dysregulation contributes to neuropathological conditions. In our studies, we demonstrated strong evidences for disease-associated miRNA expression changes during critical disease stages in brain regions vulnerable to neurodegeneration. In publication I, we gained a comprehensive picture of global miRNA expression changes in frontal cortex and cerebellum during clinical stage of sporadic Creutzfeldt–Jakob disease, the most prevalent human prion disease. We observed marked miRNA expression alterations highly changed in a regional and disease subtype-dependent manner in sporadic Creutzfeldt–Jakob disease. We additionally revealed complex impairments of key proteins involved in the miRNA silencing machinery and biogenesis that might underlie miRNA dysregulation in sporadic Creutzfeldt–Jakob disease. We clearly validated the miRNA expression signatures observed in sporadic Creutzfeldt–Jakob disease, in a mouse model highly relevant to human pathology. In cross-disease validation studies, we detected that specific sporadic Creutzfeldt–Jakob disease-regulated miRNAs are commonly altered in alternative neurodegenerative disease shedding light into potential common miRNA-related mechanisms in the neurodegenerative conditions. In publication II, we provided crucial insights into temporal miRNA expression alterations in brain regions vulnerable to early Alzheimer’s disease-type pathology. Therefore, we performed targeted expression profiling of miRNAs implicated in Alzheimer’s disease pathogenesis in the locus coeruleus, entorhinal cortex, hippocampal CA1 region and dentate gyrus during early and mid-stages of Braak neurofibrillary tangles pathology. In this way, we provided for the first time insights into crucial miRNA expression alterations in the locus coeruleus during early Alzheimer’s disease-type pathology before disease-associated neuronal death is evident. By a combination of different miRNA quantification approaches we provided a state-of-art methodology for a comprehensive screening and reliable validation of disease-associated miRNA signatures. Thereby, we emphasized the importance of a more holistic understanding in temporal, spatial and cellular aspects of miRNA alterations during neurodegenerative conditions, which will help to unravel biological consequences of miRNA dysregulation in disease. de
dc.contributor.coReferee Rizzoli, Silvio Prof. Dr.
dc.contributor.thirdReferee Llorens, Franc Dr.
dc.subject.eng Neurodegenerative diseases de
dc.identifier.urn urn:nbn:de:gbv:7-21.11130/00-1735-0000-0005-126B-F-7
dc.affiliation.institute Medizinische Fakultät
dc.subject.gokfull Neurologie - Allgemein- und Gesamtdarstellungen (PPN619876247) de
dc.subject.gokfull Neuroanatomie, Neurophysiologie, Neuropathologie (PPN619876255) de
dc.subject.gokfull Molekularbiologie {Medizin} (PPN619875186) de
dc.identifier.ppn 167862795X

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