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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.

SUBMITTER: Ewald CY 

PROVIDER: S-EPMC3374313 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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APL-1, the Alzheimer's Amyloid precursor protein in Caenorhabditis elegans, modulates multiple metabolic pathways throughout development.

Ewald Collin Y CY   Raps Daniel A DA   Li Chris C  

Genetics 20120330 2


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  ...[more]

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