title: APL-1, the Alzheimer's Amyloid precursor protein in Caenorhabditis elegans, modulates multiple metabolic pathways throughout development.
abstract: Mutations in the amyloid precursor protein (APP) gene or in genes that process APP are correlated with familial Alzheimer's disease (AD). The biological function of APP remains unclear. APP is a transmembrane protein that can be sequentially cleaved by different secretases to yield multiple fragments, which can potentially act as signaling molecules. Caenorhabditis elegans encodes one APP-related protein, APL-1, which is essential for viability. Here, we show that APL-1 signaling is dependent on the activity of the FOXO transcription factor DAF-16 and the nuclear hormone receptor DAF-12 and influences metabolic pathways such as developmental progression, body size, and egg-laying rate. Furthermore, apl-1(yn5) mutants, which produce high levels of the extracellular APL-1 fragment, show an incompletely penetrant temperature-sensitive embryonic lethality. In a genetic screen to isolate mutants in which the apl-1(yn5) lethality rate is modified, we identified a suppressor mutation in MOA-1/R155.2, a receptor-protein tyrosine phosphatase, and an enhancer mutation in MOA-2/B0495.6, a protein involved in receptor-mediated endocytosis. Knockdown of apl-1 in an apl-1(yn5) background caused lethality and molting defects at all larval stages, suggesting that apl-1 is required for each transitional molt. We suggest that signaling of the released APL-1 fragment modulates multiple metabolic states and that APL-1 is required throughout development.
authors.affiliation: Graduate Center, City University of New York, New York, New York 10016, USA.
authors.forename: Collin Y
authors.initials: CY
authors.lastname: Ewald
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Raps
authors.forename: Chris
authors.initials: C
authors.lastname: Li
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D047108:Embryonic Development / Q000235:genetics; D051858:Forkhead Transcription Factors; D015870:Gene Expression; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D018869:Heat-Shock Response; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D053858:Metabolic Networks and Pathways; D009154:Mutation; D010641:Phenotype; D021381:Protein Transport; D034622:RNA Interference; D011972:Receptor, Insulin / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C084891:APL-1 protein, C elegans; D029742:Caenorhabditis elegans Proteins; C410905:DAF-12 protein, C elegans; D051858:Forkhead Transcription Factors; D008565:Membrane Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C108831:daf-16 protein, C elegans; C107483:DAF-2 protein, C elegans; D011972:Receptor, Insulin