HOP-1, a Caenorhabditis elegans presenilin, appears to be functionally redundant with SEL-12 presenilin and to facilitate LIN-12 and GLP-1 signaling

Abstract

Mutant presenilins have been found to cause Alzheimer disease. Here, we describe the identification and characterization of HOP-1, a Caenorhabditis elegans presenilin that displays much more lower sequence identity with human presenilins than does the other C. elegans presenilin, SEL-12. Despite considerable divergence, HOP-1 appears to be a bona fide presenilin, because HOP-1 can rescue the egg-laying defect caused by mutations in sel-12 when hop-1 is expressed under the control of sel-12 regulatory sequences. HOP-1 also has the essential topological characteristics of the other presenilins. Reducing hop-1 activity in a sel-12 mutant background causes synthetic lethality and terminal phenotypes associated with reducing the function of the C. elegans lin-12 and glp-1 genes. These observations suggest that hop-1 is functionally redundant with sel-12 and underscore the intimate connection between presenilin activity and LIN-12͞ Notch activity inferred from genetic studies in C. elegans and mammals.Genetic linkage studies have identified a number of loci associated with familial Alzheimer disease (1). Two of these loci encode related multipass transmembrane proteins, presenilins 1 and 2 (PS1 and PS2). Mutations in the genes encoding PS1 and PS2 loci are dominant and fully penetrant for early onset Alzheimer disease (2-4). The presenilins are ubiquitously expressed (3, 4) and found in conjunction with intracellular membranes (5). However, the normal role of presenilins, and the mechanism by which mutant presenilins cause Alzheimer disease, are not known.Genetic studies in simple organisms offer a powerful approach to understanding the normal role of presenilins. The Caenorhabditis elegans sel-12 gene encodes a protein that displays about 50% amino acid sequence identity to PS1 and PS2 (6). Genetic analysis established that reducing or eliminating sel-12 activity causes an egg-laying defective (Egl) phenotype, and that sel-12 activity facilitates the activity of LIN-12 and GLP-1, two receptors of the LIN-12͞Notch family (6). SEL-12 appears to be a bona fide presenilin, because human PS1 and PS2 can rescue the Egl phenotype of a sel-12 mutant (7). Furthermore, the membrane topology of SEL-12 and PS1 appears to be similar (8-10). In addition to the functional and structural similarities, expression studies indicate that SEL-12 and human presenilins are expressed throughout development in many different cell types (3, 4, 7).We have identified another candidate C. elegans presenilin based on predicted amino acid sequence by searching the genomic sequence database (11,12). Here, we show that this gene, which we have named hop-1 (hop ϭ homolog of presenilin), encodes a functional presenilin, by demonstrating that HOP-1 can rescue the egg-laying defect of a sel-12 mutant. We also show that HOP-1 has characteristic features of presenilin membrane topology. Finally, we show that reducing hop-1 activity in a sel-12 mutant background results in novel phenotypes, suggesting that hop-1 and sel-12 are functionally redundant.

Suppressors of the egg-laying defective phenotype of sel-12 presenilin mutants implicate the CoREST corepressor complex in LIN-12/Notch signaling in C. elegans

“…Loss of hop-1 presenilin activity does not cause an overt phenotype, whereas loss of both hop-1 and sel-12 activity causes phenotypes that are similar to those caused by loss of lin-12 and glp-1 activity (Li and Greenwald 1997; Westlund et al 1999). However, the precise double mutant phenotype observed can be influenced by the presence of maternal presenilin activity (Westlund et al 1999 To examine whether spr-1 negatively regulates lin-12 activity during VPC specification, we first asked whether spr-1(ar200) can enhance the activity of lin-12(n302) so as to cause a Muv phenotype.…”

Moonlighting activity of presenilin in plants is independent of γ-secretase and evolutionarily conserved

“…evolution ͉ iCLiP ͉ Alzheimer's disease ͉ cytoskeleton ͉ Physcomitrella P resenilin (PS) proteins are polytopic transmembrane domain (TMD) proteins discovered independently as loci frequently mutated in familial forms of Alzheimer's disease (AD) (1-3) and as modifiers of Notch signaling (4,5). PS proteins form the catalytic center of ␥-secretase, an aspartate protease complex that cleaves type I substrates sequentially within their TMD to release soluble C-and N-terminal peptides (6,7).…”

Screening for Presenilin Inhibitors Using the Free-Living Nematode, Caenorhabditis elegans

“…6,7 Hop-1 loss-of-function mutations in sel-12 null worms are lethal, although null mutants of hop-1 are not egl. One can view these phenotypes as representing a spectrum of reductions in total presenilin function.…”

“…Three presenilin genes have been identified in C. elegans: sel-12, hop-1, and spe-4. [4][5][6][7] Loss-of-function mutations in sel-12 cause a defect in egg laying, which can be rescued by human PS1 or PS2, demonstrating that features of the presenilin protein required for function have been conserved between nematodes and humans. 5,8 Sel-12 has been shown to be required for signaling mediated by the C. elegans Notch receptor homologs, lin-12 and glp-1.…”