ArticleDisease models & mechanisms
Dictyostelium possesses highly diverged presenilin/gamma-secretase that regulates growth and cell-fate specification and can accurately process human APP: a system for functional studies of the presenilin/gamma-secretase complex.
Article in Disease models & mechanisms. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 44 citations in OpenAlex.
- Diverse Roles of the Multiple Phosphodiesterases in the Regulation of Cyclic Nucleotide Signaling inCells · 2025Review
- Plate-Based Assays for the Characterization of Mitochondrial and Cellular Phenotypes.Methods in molecular biology (Clifton, N.J.) · 2024Article
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- Nicastrin-Like, a Novel Transmembrane Protein fromMicroorganisms · 2021Article
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- Interactions and Cytotoxicity of Human Neurodegeneration- Associated Proteins Tau and α-Synuclein in the Simple ModelFrontiers in cell and developmental biology · 2021Article
- Gamma secretase orthologs are required for lysosomal activity and autophagic degradation inAutophagy · 2019Article
- Non-coding RNA influences in dementia.Non-coding RNA research · 2018Review
- Role of Presenilin in Mitochondrial Oxidative Stress and Neurodegeneration inAntioxidants (Basel, Switzerland) · 2018Review
- Presenilins as Drug Targets for Alzheimer's Disease-Recent Insights from Cell Biology and Electrophysiology as Novel Opportunities in Drug Development.International journal of molecular sciences · 2018Review
- Curcumin and derivatives function through protein phosphatase 2A and presenilin orthologues inDisease models & mechanisms · 2018Article
- Aberrant adhesion impacts early development in a Dictyostelium model for juvenile neuronal ceroid lipofuscinosis.Cell adhesion & migration · 2017Article
- Methods to Monitor and Quantify Autophagy in the Social Amoeba Dictyostelium discoideum.Cells · 2017Review
- Using the social amoeba Dictyostelium to study the functions of proteins linked to neuronal ceroid lipofuscinosis.Journal of biomedical science · 2016Review
- Non-Catalytic Roles of Presenilin Throughout Evolution.Journal of Alzheimer's disease : JAD · 2016Review
- The cryo-electron microscopy structure of γ-Secretase: towards complex assembly, substrate recognition and a catalytic mechanism.National science review · 2015Article
- Structure of nicastrin unveils secrets of γ-secretase.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Crystal structure of the γ-secretase component nicastrin.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Gamma-secretase subunits associate in intracellular membrane compartments in Arabidopsis thaliana.Journal of experimental botany · 2014Article
- An ancestral non-proteolytic role for presenilin proteins in multicellular development of the social amoeba Dictyostelium discoideum.Journal of cell science · 2014Article
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4 authors at 3 institutions in 1 country.
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Abstract
Presenilin (PS) is the catalytic moiety of the gamma-secretase complex. PS and other gamma-secretase components are well conserved among metazoa, but their presence and function in more-distant species are not resolved. Because inappropriate gamma-secretase processing of amyloid precursor protein (APP) in humans is associated with familial Alzheimer's disease, understanding essential elements within each gamma-secretase component is crucial to functional studies. Diverged proteins have been identified in primitive plants but experiments have failed to demonstrate gamma-secretase activity. We have identified highly diverged orthologs for each gamma-secretase component in the ancient eukaryote Dictyostelium, which lacks equivalents of APP, Notch and other characterized PS/gamma-secretase substrates. We show that wild-type (WT) Dictyostelium is capable of amyloidogenic processing of ectopically expressed human APP to generate amyloid-beta peptides Abeta(40) and Abeta(42); strains deficient in gamma-secretase cannot produce Abeta peptides but accumulate processed intermediates of APP that co-migrate with the C-terminal fragments alpha- and beta-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 gamma-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/gamma-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.
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