Dictyostelium possesses highly diverged presenilin/γ-secretase that regulates growth and cell-fate specification and can accurately process human APP: a system for functional studies of the presenilin/γ-secretase complex

Abstract

SUMMARY Presenilin (PS) is the catalytic moiety of the γ-secretase complex. PS and other γ-secretase components are well conserved among metazoa, but their presence and function in more-distant species are not resolved. Because inappropriate γ-secretase processing of amyloid precursor protein (APP) in humans is associated with familial Alzheimer’s disease, understanding essential elements within each γ-secretase component is crucial to functional studies. Diverged proteins have been identified in primitive plants but experiments have failed to demonstrate γ-secretase activity. We have identified highly diverged orthologs for each γ-secretase component in the ancient eukaryote Dictyostelium, which lacks equivalents of APP, Notch and other characterized PS/γ-secretase substrates. We show that wild-type (WT) Dictyostelium is capable of amyloidogenic processing of ectopically expressed human APP to generate amyloid-β peptides Aβ40 and Aβ42; strains deficient in γ-secretase cannot produce Aβ peptides but accumulate processed intermediates of APP that co-migrate with the C-terminal fragments α- and β-CTF of APP that are found in mammalian cells. We further demonstrate that Dictyostelium requires PS for phagocytosis and cell-fate specification in a cell-autonomous manner, and show that regulation of phagocytosis requires an active γ-secretase, a pathway suggested, but not proven, to occur in mammalian and Drosophila cells. Our results indicate that PS signaling is an ancient process that arose prior to metazoan radiation, perhaps independently of Notch. Dictyostelium might serve to identify novel PS/γ-secretase signaling targets and provide a unique system for high-throughput screening of small-molecule libraries to select new therapeutic targets for diseases associated with this pathway.