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@PHDTHESIS{Jackson:278574,
      author       = {Jackson, Joshua},
      title        = {{I}dentification of compensatory mechanisms and disease
                      pathways in mitochondrial disease and synucleinopathy},
      school       = {Rheinische Friedrich-Wilhelms-Universität Bonn},
      type         = {Dissertation},
      reportid     = {DZNE-2025-00607},
      pages        = {97 p.},
      year         = {2025},
      note         = {Dissertation, Rheinische Friedrich-Wilhelms-Universität
                      Bonn, 2025},
      abstract     = {Mitochondria 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.},
      cin          = {AG Bano},
      cid          = {I:(DE-2719)1013003},
      pnm          = {351 - Brain Function (POF4-351)},
      pid          = {G:(DE-HGF)POF4-351},
      typ          = {PUB:(DE-HGF)11},
      urn          = {urn:nbn:de:hbz:5-82889},
      url          = {https://pub.dzne.de/record/278574},
}