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.identifier.uri | http://dx.doi.org/10.53846/goediss-7673 | |
dc.identifier.uri | http://dx.doi.org/10.53846/goediss-7673 | |
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 | |