Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease for which there is currently no effective treatment. Therefore, it is essential to investigate the mechanisms leading to motor neuron death to find potential therapeutic targets. In this thesis, we deepen our understanding of 3 proteins involved in the pathogenesis of ALS (Fused in Sarcoma -FUS, Vesicle-associated Membrane Protein B -VAPB, and the ephrin receptor A4-EPHA4) by analyzing their effects when mutated, absent, or when their activity is inhibited. There is increasing evidence that suggests that overlapping mechanisms play a role in neurodegeneration and cell transformation. Therefore, we investigated these ALS -related proteins in neurodegeneration and medulloblastoma development. We describe that protein translation –a well-known mechanism that cells upregulate when transformed- is one of the first and most fundamental pathways decreased in cells with ALS -related mutations. We also show that interferon-gamma (IFN-y) upregulates translation-associated genes, specifically in ALS MNs. Regarding the function of ALS-associated proteins in medulloblastoma, we reveal novel roles for VAPB and EPHA4 in tumor progression. In summary, we provide evidence to support the hypothesis that neurodegeneration and tumorigenesis are the results of the same deregulated signaling pathways, which could lead to a better understanding of these devastating diseases and generate new intervention strategies to improve the lives of patients in the future.
|Qualification||Doctor of Philosophy|
|Place of Publication||[Groningen]|
|Publication status||Published - 2022|