Nicastrin is required for Presenilin-mediated transmembrane cleavage in Drosophila

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Abstract
The transmembrane glycoprotein Nicastrin was identified in a complex with the multipass membrane protein Presenilin1. Presenilin mediates transmembrane cleavage of single-pass transmembrane proteins with short extracellular domains2, including the ligand-activated form of the receptor Notch3,4,5 and β-amyloid precursor protein (β-APP)6,7. Transmembrane cleavage of Notch is essential for signal transduction3,4,5, and transmembrane cleavage of β-APP generates pathogenic amyloid peptides implicated in Alzheimer's disease8. Here, we investigate the requirement for Nicastrin in Presenilin-mediated transmembrane cleavage. We show that, in Drosophila, loss of Nicastrin activity blocks the accumulation of Presenilin associated with the apical plasma membrane, abolishes Presenilin-dependent cleavage of the transmembrane domains of Notch and β-APP, and abrogates Notch signal transduction.