| Presenilin (PS) is the catalytic moiety of the gamma-secretase complex. PS/gamma-secretase components are well-conserved among metazoa, but the presence and function of related factors in more distant species are not resolved. We have identified highly diverged, putative orthologs for each PS/gamma-secretase component in the ancient eukaryote Dictyostelium discoideum that lacks endogenous amyloid precursor protein (APP), Notch, and other characterized PS/gamma-secretase substrates. To elucidate molecular mechanisms intrinsic to presenilin function or dysfunction, we created single and double mutants for the gamma-secretase component genes. WT Dictyostelium is capable of amyloidogenic processing of ectopically expressed human APP to generate Abeta40 and Abeta42 peptides; strains deficient in gamma-secretase components cannot produce Abeta peptides but accumulate "ectodomain shedding" intermediates of APP that are identical to alpha- and beta-C-terminal fragments (CTFs) of mammalian cells. We further demonstrate that Dictyostelium require PS/gamma-secretase for phagocytic growth and prespore/spore fate specification in a cell-autonomous manner, demonstrating that PS-signaling is an ancient process that arose prior to metazoan radiation. Finally, we identified proteins that have direct interactions with PS, suggesting there are many potential pathways that involve this protein in Dictyostelium with implications for all metazoa. |
