Jonas Johannes Papendorf

• The proteasome is one of the major cellular protein degradation systems. The respective substrates include cell cycle regulators, kinases, transcription factors, antigens and enzymes. As such the proteasome plays a major role in cell function, survival and proliferation. Another key target of the proteasome are damaged and misfolded proteins as well as those proteins that are no loner required. Therefore, the proteasome is key in maintaining proteostasis, which describes the balance between the synthesis of new proteins and the removal of damaged, old and misfolded ones. Several factors such as ageing, disease and certain medications can impair proteasome function and thus disturb cellular proteostasis. The current work focused on novel genetic mutations in the various subunits constituting the proteasome. The proteasomal mutations were found to cause two very distinct disease phenotypes, PRAAS (an autoinflammatory disorder) and NDD (neurodevelopmental delay). The novel mutations discussed in this work were found to impair proteasome function through a variety of mechanisms and lead to decreased proteolytic capacity in the cells of the patients, resulting in a disturbance of cellular proteostasis and disease manifestation.