000278574 001__ 278574
000278574 005__ 20251212143201.0
000278574 0247_ $$2URN$$aurn:nbn:de:hbz:5-82889
000278574 037__ $$aDZNE-2025-00607
000278574 041__ $$aEnglish
000278574 1001_ $$0P:(DE-2719)2814190$$aJackson, Joshua$$b0$$eFirst author
000278574 245__ $$aIdentification of compensatory mechanisms and disease pathways in mitochondrial disease and synucleinopathy
000278574 260__ $$c2025
000278574 300__ $$a97 p.
000278574 3367_ $$2DataCite$$aOutput Types/Dissertation
000278574 3367_ $$2ORCID$$aDISSERTATION
000278574 3367_ $$2BibTeX$$aPHDTHESIS
000278574 3367_ $$02$$2EndNote$$aThesis
000278574 3367_ $$0PUB:(DE-HGF)11$$2PUB:(DE-HGF)$$aDissertation / PhD Thesis$$bphd$$mphd$$s1758632084_10852
000278574 3367_ $$2DRIVER$$adoctoralThesis
000278574 502__ $$aDissertation, Rheinische Friedrich-Wilhelms-Universität Bonn, 2025$$bDissertation$$cRheinische Friedrich-Wilhelms-Universität Bonn$$d2025$$o2025-05-13
000278574 520__ $$aMitochondria play vital roles in a variety of processes such as cellular metabolism, intracellular signalling and cell death. Defects in mitochondria can lead to inherited metabolic disorders and neurodegenerative diseases. There is often a poor genotype-to-phenotype correlation in mitochondrial diseases, with distinct mutations that lead to a wide variety of clinical manifestations, age of onset and disease severity. This heterogeneity of symptoms, in combination with a relatively low frequency in the population, makes the development of novel treatments particularly challenging.In invertebrates and some mouse models of mitochondrial diseases, inhibition of the mitochondrial oxidative phosphorylation (OXPHOS) can lead to a paradoxical lifespan extension through the engagement of compensatory mechanisms. As an explanation of this phenomena, the “mitochondrial threshold effect theory” states that mitochondrial dysfunction below a certain threshold promotes stress resilience and metabolic rewiring, leading to enhanced longevity. However, if damage exceeds a certain threshold, animals develop disease. In a human context, a better understanding of the “mitochondrial threshold effect” may explain some of the molecular signatures and variable disease traits observed in patients. We sought to explore the compensatory mechanisms that organisms activate in response to the inhibition of OXPHOS using Caenorhabditis elegans as a genetically tractable model, in combination with mouse and human cells. Our goals were to investigate the underlying molecular mechanisms that contribute to mitochondrial dysfunction and neurodegenerative processes.By performing a cross-species analysis, we identified VPS-39/VPS39 and  SPL-1/SGPL1 to be part of the molecular mechanisms that compensate for mitochondrial dysfunction. In the context of neurodegenerative processes, we found that the actin nucleation promoting factor WSP-1/N-WASP is a disease modifier that contributes to mitochondrial dysfunction and proteotoxicity. Together, these results build on our growing understanding of the mechanisms that counteract mitochondrial dysfunction and pathogenic processes.
000278574 536__ $$0G:(DE-HGF)POF4-351$$a351 - Brain Function (POF4-351)$$cPOF4-351$$fPOF IV$$x0
000278574 8564_ $$uhttps://hdl.handle.net/20.500.11811/13111
000278574 8564_ $$uhttps://pub.dzne.de/record/278574/files/DZNE-2025-00607_Restricted.pdf
000278574 8564_ $$uhttps://pub.dzne.de/record/278574/files/DZNE-2025-00607_Restricted.pdf?subformat=pdfa$$xpdfa
000278574 909CO $$ooai:pub.dzne.de:278574$$pVDB
000278574 9101_ $$0I:(DE-588)1065079516$$6P:(DE-2719)2814190$$aDeutsches Zentrum für Neurodegenerative Erkrankungen$$b0$$kDZNE
000278574 9131_ $$0G:(DE-HGF)POF4-351$$1G:(DE-HGF)POF4-350$$2G:(DE-HGF)POF4-300$$3G:(DE-HGF)POF4$$4G:(DE-HGF)POF$$aDE-HGF$$bGesundheit$$lNeurodegenerative Diseases$$vBrain Function$$x0
000278574 9141_ $$y2025
000278574 9201_ $$0I:(DE-2719)1013003$$kAG Bano$$lAging and Neurodegeneration$$x0
000278574 980__ $$aphd
000278574 980__ $$aVDB
000278574 980__ $$aI:(DE-2719)1013003
000278574 980__ $$aUNRESTRICTED