One approach to assigning a function to presenilin 1 (PS1) is to identify those proteins with which it interacts.
The specific aims are based upon our discovery of a novel brain protein which interacts with the extended hydrophilic """"""""loop"""""""" region (residues 263-407) of PS1. The interacting gene product we discovered is a novel member of a gene family represented by its prototypic members, beta-catenin in vertebrates, and Armadillo in Drosophila. These proteins have dual roles: they are components of the adherens junction, an adhesive structure which forms between homotypic cells, and intermediaries in the Wingless/Wnt signaling pathway which is involved in body axis formation and segment polarity. We have termed the PS1 interacting gene, beta-catenin, because it shares with other catenins a series of 42 amino acid imperfect repeats and our preliminary evidence suggests it is resident in the adherens junction. Another reason this interaction is potential significant is the growing body of evidence that presenilin has a role in early development, particularly in relation to the Notch pathway which specifies cell fate. However, the sound genetic evidence of a functional relationship between Notch and presenilin does not reveal the specific proteins which interact with these gene products. Remarkably, a downstream element in the Wg/Wnt pathway, specifically the Disheveled gene, imposes an inhibitory regulation on Notch. Therefore the PS1 interacting gene which resembles known family members of the Notch regulatory pathway, Wnt/Wg may represent a pivotal control point.
Our aims will characterize the function of delta-catenin and address the hypothesis that modulation of upstream elements in the delta-catenin signaling pathway will alter the levels of Abeta produced by the cell. We will conclusively demonstrated whether delta-catenin is resident in the adherns junction, the relationship of these junctions to synapses in the CNS, and the regulation and control elements which target delta-catenin to the adherns junction. We will determine whether delta-catenin lies in the Wnt signaling pathway by assessing the effects of Wnt signals on delta- catenin stability and searching for interactive proteins. We will attempt to assign an early developmental role to delta-catenin by preparing a disrupter mouse. Finally, we will establish a relationship between delta- catenin and Alzheimer's disease by determining whether PS-1 mutations alter the interaction with delta-catenin and whether delta-catenin lies in a pathway capable of regulating APP metabolism and Abeta generation.
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