000269355 001__ 269355
000269355 005__ 20240522105922.0
000269355 0247_ $$2URN$$ahttps://nbn-resolving.org/urn:nbn:de:hbz:5-76077
000269355 0247_ $$2URN$$anbn:de:hbz:5-76077
000269355 0247_ $$2URN$$aurn:nbn:de:hbz:5-76077
000269355 037__ $$aDZNE-2024-00523
000269355 041__ $$aEnglish
000269355 1001_ $$0P:(DE-2719)2812579$$aHornberger, Annika$$b0$$udzne
000269355 245__ $$aThe yeast prion domain Sup35 NM models features of human neurodegenerative diseases in vivo$$f - 2024-04-29
000269355 260__ $$bUniversitäts- und Landesbibliothek Bonn$$c2024
000269355 300__ $$a97 p.
000269355 3367_ $$2DataCite$$aOutput Types/Dissertation
000269355 3367_ $$2ORCID$$aDISSERTATION
000269355 3367_ $$2BibTeX$$aPHDTHESIS
000269355 3367_ $$02$$2EndNote$$aThesis
000269355 3367_ $$0PUB:(DE-HGF)11$$2PUB:(DE-HGF)$$aDissertation / PhD Thesis$$bphd$$mphd$$s1716368345_17941
000269355 3367_ $$2DRIVER$$adoctoralThesis
000269355 502__ $$aDissertation, Rheinische Friedrich-Wilhelms-Universität Bonn, 2024$$bDissertation$$cRheinische Friedrich-Wilhelms-Universität Bonn$$d2024$$o2024-04-29
000269355 520__ $$aIn neurodegenerative diseases, such as prion diseases and Alzheimer’s disease, disease-associated proteins misfold and form amyloid deposits that progressively invade the CNS, leading to severe neurodegeneration. Accumulating evidence suggests that amyloid proteins propagate in a prion-like, self-perpetuating manner, but the mechanism of aggregate multiplication in mammals remains unclear. Amyloid deposits are associated with neurodegeneration and can induce a toxic gain-of-function or loss-of-function phenotype. Yet, the contribution of both effects to neurodegeneration is not fully understood. Surprisingly, the same pathogenic protein can aggregate into different structural variants that, similar to prion strains, may cause heterogenous clinical symptoms. However, how the amyloid structure can influence disease progression needs to be elucidated. Previously, our group established the NM-HA mouse model that expresses the hemagglutinin-tagged prion domain NM of the Saccharomyces cerevisiae prion Sup35 that behaves like a prion in mammalian cells. As NM does not possess a cellular function in mammals, it can be used to study the gain-of-function of protein aggregates in the absence of loss-of-function effects. In this project, we used the NM-HA mouse line to investigate the ability of fibril-induced NM-HA aggregates to propagate in the mammalian brain, and thus to model human prion-like proteins. Additionally, we tested if the gain-of-function of intracellular NM-HA aggregates can cause neurodegeneration and compared the disease pathogenesis induced by two different NM fibril conformers. Here we show that the intracranial injection of NM fibrils into NM-HA animals induces progressive NM-HA aggregation, demonstrating that yeast NM prions can replicate in mice. Interestingly, our data points to the involvement of the chaperone valosin-containing protein (VCP) as potential NM prion disaggregase in this process. NM-HA aggregates seeded by the NM fibril variants spread from the hippocampus to similar neuroanatomically connected regions, with striking similarity to pathologies observed in wildtype mice challenged with disease-associated protein aggregates. Fibril-injected animals develop mild cognitive decline, likely caused by neuronal loss in hippocampal subregions with prominent NM-HA deposition. Remarkably, neurodegeneration is accompanied by local microgliosis and astrogliosis. Hence, a non-mammalian and non-disease-related protein is able to cause neurodegeneration upon aggregation in mice, likely via a neurotoxic gain-of-function effect. As fibril-injected NM-HA mice recapitulate key aspects of the pathogenesis of human neurodegenerative disorders, our data argue that mechanisms underlying intracellular amyloid fragmentation, dissemination, and toxicity might be shared between amyloidogenic proteins.
000269355 536__ $$0G:(DE-HGF)POF4-352$$a352 - Disease Mechanisms (POF4-352)$$cPOF4-352$$fPOF IV$$x0
000269355 588__ $$aDataset connected to DataCite
000269355 650_7 $$2Other$$aSup35
000269355 650_7 $$2Other$$aNM
000269355 650_7 $$2Other$$aPrion
000269355 650_7 $$2Other$$aAusbreitung
000269355 650_7 $$2Other$$aNeurodegeneration
000269355 650_7 $$2Other$$aMaus
000269355 650_7 $$2Other$$addc:500
000269355 650_7 $$2Other$$addc:570
000269355 650_7 $$2Other$$addc:610
000269355 8564_ $$uhttps://hdl.handle.net/20.500.11811/11551
000269355 8564_ $$uhttps://pub.dzne.de/record/269355/files/DZNE-2024-00523_Restricted.pdf
000269355 8564_ $$uhttps://pub.dzne.de/record/269355/files/DZNE-2024-00523_Restricted.pdf?subformat=pdfa$$xpdfa
000269355 909CO $$ooai:pub.dzne.de:269355$$pVDB
000269355 9101_ $$0I:(DE-588)1065079516$$6P:(DE-2719)2812579$$aDeutsches Zentrum für Neurodegenerative Erkrankungen$$b0$$kDZNE
000269355 9131_ $$0G:(DE-HGF)POF4-352$$1G:(DE-HGF)POF4-350$$2G:(DE-HGF)POF4-300$$3G:(DE-HGF)POF4$$4G:(DE-HGF)POF$$aDE-HGF$$bGesundheit$$lNeurodegenerative Diseases$$vDisease Mechanisms$$x0
000269355 9141_ $$y2024
000269355 9201_ $$0I:(DE-2719)1013004$$kAG Vorberg$$lPrion Cell Biology$$x0
000269355 980__ $$aphd
000269355 980__ $$aVDB
000269355 980__ $$aI:(DE-2719)1013004
000269355 980__ $$aUNRESTRICTED