Examining requirement for formation of functional Presenilin proteins and their processing events in vivo

Presenilin (Psn) is a multipass transmembrane protein that functions as the catalytic subunit of γ‐secretase for mediating intramembrane cleavage of type 1 transmembrane proteins. Normally active Psn is in the form of a heterodimer composed by its N‐terminal and C‐terminal fragments that are generated from a Presenilinase‐mediated endoproteolytic cleavage within its large cytosolic loop during assembly of the protease complex. Using the Psn forms that either bypass or disable Presenilinase‐mediated endoproteolysis, and a Psn form that has most of the large cytosolic loop deleted, we have established an in vivo system to enable investigations of Psn functional domains in Drosophila . We show that the Presenilinase‐mediated endoproteolytic event is not essential for producing Psn activity during animal development, and is regulated by integrity of the large cytosolic loop of Psn in Drosophila . The Psn transgenic flies described here could be applied to a broad range of studies on Psn functioning and its related γ‐secretase activity at any developmental stage. genesis 47:161–168, 2009. © 2009 Wiley‐Liss, Inc.