Exploring extracellular protein aggregation and its regulation

Extracellular protein aggregation is a pathological hallmark associated with devastating diseases such as Alzheimer’s disease and type II diabetes. Inside cells, protein quality control (PQC) mechanisms maintain a balanced and functional proteome. In contrast, little is known about protective mechanisms acting outside cells. Until recently, only a few extracellular chaperones and proteases were shown to limit extracellular protein aggregation. We developed a Caenorhabditis elegans model to study protein aggregation in the extracellular space. We performed a systematic analysis to identify the extracellular protein homeostasis network in C. elegans and discovered 57 novel extracellular regulators of protein aggregation of which half have potential human orthologues. Building on these findings, first we propose to investigate the mechanisms of extracellular PQC by characterizing chaperone and protease activities among C. elegans extracellular regulators and human orthologues. Second, we will determine how extracellular PQC promotes healthy ageing and host defence against pathogens in C. elegans. Finally, we will translate our finding into mice and examine if extracellular regulators prevent Alzheimer’s disease associated amyloid-β aggregation and delay mammalian brain ageing. I expect these studies to be a milestone in our understanding of how organisms keep proteins functional outside their constituent cells to maintain health.