Because presenilin was discovered in positional cloning experiments involving large familial Alzheimer's disease kindreds, there were no previous data concerning its biological function. As a result, many groups have used a variety of techniques to garner clues regarding the function of this novel gene, which bears a key relationship to Alzheimer's disease.
Since the cloning of presenilin, one of the important functional clues to emerge was the critical role that presenilin plays in development. This insight derived from presenilin 1 "knockout" animals. The next step in further understanding the function of presenilin is the identification of the verification of binding partners. The lengthy procedures involved in discovering these interactors and more importantly in authenticating them accounts for the two-year interval between the discovery of presenilin and the reporting of several interactors. Before this meeting the putative interactive PS1 proteins were β-catenin, δ-catenin, actin-binding protein, and the amyloid precursor protein. All of these interactors have proponents and nay-sayers. Described in the Molecular Pathology II session, the new interactors were CLIP-170 (with PS1) from the Robakis group, and calsenilin (with PS1 and PS2) from the Wasco group. Other presentations not in this session described an interaction between Notch and PS1 by Alison Goate's group and an interaction between sorcin and PS2 by Tae-Wan Kim in the Tanzi group. Together these proteins constitute a thicket of new clues with few if any clear directions concerning which of the interactions, if any, will play a role in the disease pathogenesis. All of them are worthy of further pursuit.
Tezapsidis N et al. (Abstract 1257) reported that one PS1 mutation (E280A) showed an increased binding to CLIP170. This protein, first discovered by Tomas Kreis in the early nineties, has 1390 amino acids with a large coiled coil α helical domain in the central part of the protein. Fifty-seven amino acids at the amino terminus bind to vesicles and an acidic carboxy terminus binds to microtubules. Thus, CLIP170 lies at a most interesting interface between endocytosis and the microtubules. In addition to the in vitro interaction, the authors described co-localization of a myc-CLIP 170 transfectant and PS1 in 5YSY cells. This cell line is a human neuroblastoma line.
Choi E et al. (Abstract 1258) described how calsenilin was discovered in a two-hybrid screen using the carboxy terminus of PS2 as the bait. Confirmation of the interaction was by coimmunoprecipitation both ways in transfected COS cells. The authors were also able to coimmunoprecipitate calsenilin and PS1. The high degree of homology between the PS1 and PS2 amino termini probably accounts for the ability of both proteins to form a complex with calsenilin. In contrast the lack of homology between the PS1 and PS2 loop regions has made the identification of common interactors with this region more problematic. When transfected, calsenilin shows a cytoplasmic distribution, but following co-transfection with PS2 the complex gets recruited to the endoplasmic reticulum and the Golgi. Although a novel gene, calsenilin is a member of the recoverin family. One characteristic of the family is the presence of EF hand motifs; there are four in calsenilin. The authors demonstrated that calsenilin binds calcium by showing a mobility shift with and without EGTA and calcium 45 overlay techniques. Interestingly, the protein is expressed specifically in the brain by Nothern blots and in both neurons and glia by in situ hybridization.
Together, these new interactors all offer the potential for new insights into presenilin biology and possibility.—Kenneth S. Kosik
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