Investigation into protein quality control pathways in Dictyostelium discoideum

Abstract Protein aggregation is a hallmark of at least 71 diseases. Protein aggregates are caused by an imbalance in protein homeostasis resulting in the accumulation of misfolded proteins. One major question in biomedical research is: How do cells recognize and deal with misfolded proteins? My laboratory has taken a unique approach to answering this question. Instead of studying protein aggregation in model organisms where proteins readily aggregate, we have identified Dictyostelium discoideum (Dictyostelium) as a proteostatic outlier, highly resistant to protein aggregation. Using this unique feature of Dictyostelium we are working to identify how nature has dealt with the problem of protein aggregation. Once we determine the mechanisms Dictyostelium utilize to suppress protein aggregation we plan to determine if this information can be used to develop therapeutic strategies. In the next five years our goal is to have a comprehensive analysis of factors that suppress protein aggregation in Dictyostelium. Factors that suppress protein aggregation in Dictyostelium will then be tested to determine if they can be used to treat human diseases caused by protein aggregation. In addition to our work on identifying how Dictyostelium evades protein aggregation we are also interested in what biological role pathways that suppress protein aggregation play in Dictyostelium biology. One particular area of interest is in Dictyostelium’s developmental cycle where single cellular amoeba transition to multicellular fruiting body. This developmental cycle is of interest because the initial gene that we identified as a suppressor of protein aggregation is part of a large gene family found only in Dictyostelium discoideum and Dictyostelium purpureum, two closely related organisms that undergo this developmental process. This gene family is developmentally regulated with most genes being transcribed in short bursts at time points during and after Dictyostelium becomes multicellular. In the coming years we want to understand what role this protein family plays in Dictyostelium development to determine if suppression of protein aggregation plays a critical role in Dictyostelium development.