Identifying genes that interact with Drosophila presenilin and amyloid precursor protein

Abstract

The gamma-secretase complex is involved in cleaving transmembrane proteins such as Notch and one of the genes targeted in Alzheimer's disease known as amyloid precursor protein (APP). Presenilins function within the catalytic core of gamma-secretase, and mutated forms of presenilins were identified as causative factors in familial Alzheimer's disease. Recent studies show that in addition to Notch and APP, numerous signal transduction pathways are modulated by presenilins, including intracellular calcium signaling. Thus, presenilins appear to have diverse roles. To further understand presenilin function, we searched for Presenilin-interacting genes in Drosophila by performing a genetic modifier screen for enhancers and suppressors of Presenilin-dependent Notch-related phenotypes. We identified 177 modifiers, including known members of the Notch pathway and genes involved in intracellular calcium homeostasis. We further demonstrate that 53 of these modifiers genetically interacted with APP. Characterization of these genes may provide valuable insights into Presenilin function in development and disease.

Presenilins Promote the Cellular Uptake of Copper and Zinc and Maintain Copper Chaperone of SOD1-dependent Copper/Zinc Superoxide Dismutase Activity

“…Our findings therefore implicate PS in the expression or stability of CCS by a mechanism that is still uncertain. This may reflect a functional, two-way interaction because a recent screen to identify genes that interact with Drosophila presenilin (Psn) identified CCS via its ability to suppress a Psnmediated dominant negative phenotype (42). In light of our findings, it is notable that BACE1 binds Cu ϩ and interacts with CCS, and BACE1 expression reduces the activity of SOD1 (43).…”

“…Although many aspects of the uptake process remain uncertain, evidence suggests that both Cu 2ϩ and Zn 2ϩ enter cells by binding to copper transporter 1 or a ZIP on the surface and are then ferried within an endosome. Notably, like CCS, ZIP1 also rescued the dominant negative Psn phenotype in Drosophila (42). We hypothesize that PS is involved in handling this metal intake endosome through autophagic pathways that have recently come to light (52).…”

“…This has important implications for considering the mechanism underlying PS-facilitated metal uptake because the divalent metal transporter 1 is a proton-dependent cation pump that relies on vATPase-dependent acidification (53). Intriguingly, a vATPase, Vha55 was also on the list of genes that could rescue the dominant negative Psn phenotype in Drosophila (42). Divalent metal transporter 1 mediates the cellular import of nonheme Fe 2ϩ but also transports other divalent metal ions, including Cu 2ϩ and Zn 2ϩ (54).…”

Modeling Amyloid Diseases in Fruit Fly Drosophila Melanogaster

“…Notably, 58 modifiers interacted with АРР, including those involved in calcium signaling. These results provide strong evidence for a link between presenilins, APP, and calcium homeostasis, and suggest that these may play an important role in AD pathogenesis [van de Hoef et al, 2009].…”

FKBP14is an essential gene that regulates Presenilin protein levels and Notch signaling inDrosophila

“…Further, many of the known -secretase targets and pathways are also conserved, making Drosophila a useful model with which to identify novel PSN interactors and regulatory mechanisms. We previously carried out a screen for modifiers of Drosophila Presenilin (Psn) and APP (van de Hoef et al, 2009) and found that mutations in FKBP14 could suppress the phenotype associated with overexpression of Psn (van de Hoef et al, 2009).…”