Abstract:
The misfolding of specific proteins and their accumulation in insoluble aggregates has long been recognized as a pathological hallmark of several neurodegenerative diseases. In recent years, widespread protein aggregation occurring during healthy aging has become a hot topic of research. However, to this date little is known about the regulation of this aggregation, the tissue‐specificity and the consequences in a disease context. This thesis answers several questions about different aspects of protein aggregation with aging and in disease. Notably, we analysed the solubility of RNA‐binding proteins that are important for the formation of stress granules (sgRBPs) in the nematode Caenorhabditis elegans (C. elegans). We showed the impact of sgRBP insolubility on organismal health and the importance of maintaining their solubility in long‐lived animals. We identified regulators of sgRBP aggregation. In addition, we showed that aggregation‐prone sgRBPs are highly prone to interact with other proteins and that this co‐localization can influence aggregation patterns or protein localization. Furthermore, we analysed the tissue‐specificity of the regulation of age‐related protein aggregation. Disruption of the protein‐quality control network has contrasting effects on protein aggregation in different tissues, surprisingly reducing age‐related protein aggregation in the pharyngeal muscle of C. elegans. Specifically, we showed that impaired proteinquality control prevented the accumulation of newly synthesized aggregation‐prone proteins. Additionally we demonstrated how screening approaches identifying mutations that influence disease‐associated phenotypes, like protein aggregation in C. elegans, can help prioritise variants found by whole exome sequencing in large cohorts of patients with Parkinson’s disease. To validate promising candidates found to be influencing protein aggregation in C. elegans, we have established a cell culture model of age‐related protein aggregation. In conclusion, these findings give important insights into mechanism and regulation of age‐related protein insolubility and highlight the importance of age‐related protein aggregation for neurodegenerative diseases.
