Clues to γ-secretase, huntingtin and Hirano body normal function using the model organism Dictyostelium discoideum

Dictyostelium discoideum is a species of soil-living amoeba belonging to the Kingdom Amoebozoa and phylum Mycetozoa. Dictyostelium, or social amoeba, is a eukaryote that when starved, transitions from individual, self-sustainable professional phagocytes into a highly coordinated developmental program (Figure 1a). During this period of multicellular development, the cells execute a series of morphological changes that proceed in defined stages over a 24 h period to form a bona fide multicellular organism. During the earliest developmental stage, cells secrete, and undergo chemotaxis toward cyclic adenosine monophosphate (cAMP) to form aggregation territories. The secretion of cAMP promotes a G protein-coupled receptor signaling cascade that results in the formation of discrete mounds containing as many as 100,000 cells [1,2]. Cells within the mound remain motile and are directed to differentiate into either prestalk or prespore cells, leading to morphogenetic changes yielding a multicellular stalk, supporting a ball of encapsulated dormant spores [3]. The entire process is clearly depicted in Figure 1b by scanning electron microscopy and although the life cycle appears simplistic, the entire process is complex with still many unresolved questions including how do cells secrete cAMP, regulate organism size, and initiate cell-fate choices to name but a few. Nevertheless, it is becoming clearer that Dictyostelium possesses signal-transduction pathways that are closely related to metazoans. Yet, with at least one major and exploitable fundamental difference: when animals undergo embryogenesis, they develop through coordinated cell division, morphogenetic movements and differentiation followed by growth of the organism. In contrast, Dictyostelium growth precedes development. This simplifies developmental studies and provides a novel route to examine with exceptional cellular clarity biological functions including cytokinesis, endocytosis, secretion, protein trafficking, i