Research Groups

Prion-like proteins in Dictyostelium discoideum

Many compartment-forming proteins carry prion-like domains, which cause neurodegeneration and protein misfolding diseases in humans. However, why do these diseases never affect young children and only manifest with increasing age? There have to be control mechanisms in place that keep these proteins under control in young cells.

To investigate this question, we started to work with the social ameba Dictyostelium discoideum. D. discoideum has the highest content of prion-like proteins of all organisms investigated to date. Remarkably, prion-like proteins remain soluble in and are innocuous to D. discoideum, in contrast to other organisms, where they form cytotoxic aggregates (Malinovska et al., 2015). However, when exposed to conditions that compromise specific proteostasis mechanisms, these proteins aggregate and become cytotoxic. This indicates that D. discoideum has undergone specific adaptations to control its aggregation-prone prion-like proteome (Figure 1). Thus, we predict that D. discoideum will be a valuable model organism to identify and characterize the molecular mechanisms regulating prion-like proteins.

<b>Figure 1.</b> Molecular mechanisms controlling protein aggregation in D. discoideum. D. discoideum has evolved at least two mechanisms to control protein aggregation. During normal growth conditions, proteins are kept soluble by molecular chaperones and can be degraded in the nucleus. The disaggregase Hsp101, probably in combination with other chaperones, can rescue stress-induced protein aggregation and restore cellular integrity.

Future Plans:

To cope with the overabundance of prion-like aggregation-prone proteins, Dictyostelium has undergone specific adaptations in its proteostasis network (Malinovska et al., 2015). In the future, we will characterize the molecular machinery that regulates the formation and subcellular distribution of prion-like protein aggregates in vegetative cells and during development. The goal is to establish Dictyostelium as a new model organism to study the functional role of prion-like proteins and their interaction with the proteostasis machinery.