Abstract
While the Amyloid Precursor Protein (APP) plays a central role in Alzheimer's disease, its cellular function still remains largely unclear. It was our goal to establish APP function which will provide insights into APP's implication in Alzheimer's disease. Using our recently developed proteo-liposome assay we established the interactome of APP's intracellular domain (known as AICD), thereby identifying novel APP interactors that provide mechanistic insights into APP function. By combining biochemical, cell biological and genetic approaches we validated the functional significance of one of these novel interactors. Here we show that APP binds the PIKfyve complex, an essential kinase for the synthesis of the endosomal phosphoinositide phosphatidylinositol-3,5-bisphosphate. This signalling lipid plays a crucial role in endosomal homeostasis and receptor sorting. Loss of PIKfyve function by mutation causes profound neurodegeneration in mammals. Using C. elegans genetics we demonstrate that APP functionally cooperates with PIKfyve in vivo. This regulation is required for maintaining endosomal and neuronal function. Our findings establish an unexpected role for APP in the regulation of endosomal phosphoinositide metabolism with dramatic consequences for endosomal biology and important implications for our understanding of Alzheimer's disease.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyloid beta-Protein Precursor / chemistry
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Amyloid beta-Protein Precursor / genetics
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Amyloid beta-Protein Precursor / metabolism*
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Animals
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Animals, Genetically Modified
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Caenorhabditis elegans / genetics
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Caenorhabditis elegans / metabolism
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Caenorhabditis elegans Proteins / chemistry
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Caenorhabditis elegans Proteins / genetics
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Caenorhabditis elegans Proteins / metabolism
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Endosomes / metabolism
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HeLa Cells
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Humans
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins / chemistry
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mutation
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Neurons / metabolism
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Phosphatidylinositol 3-Kinases / chemistry
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphatidylinositols / metabolism
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Phosphotransferases (Alcohol Group Acceptor) / chemistry
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Phosphotransferases (Alcohol Group Acceptor) / genetics
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Phosphotransferases (Alcohol Group Acceptor) / metabolism
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Protein Interaction Domains and Motifs
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Vacuoles / metabolism
Substances
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APL-1 protein, C elegans
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Amyloid beta-Protein Precursor
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Caenorhabditis elegans Proteins
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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Phosphatidylinositols
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Recombinant Proteins
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VAC14 protein, human
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PPK-3 protein, C elegans
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Phosphotransferases (Alcohol Group Acceptor)
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PIKFYVE protein, human