Human presenilin-1, but not familial Alzheimer's disease (FAD) mutants, facilitate Caenorhabditis elegans Notch signalling independently of proteolytic processing.
The majority of cases with familial Alzheimer's disease (FAD) are linked to mutations of the presenilin (PS) genes. These genes show considerable sequence similarity to the sel-12 gene of Caenorhabditis elegans, which has been postulated to function in the facilitated signalling by lin-12 and glp-1. In order to analyse the functional conservation of the presenilins, we introduced the human PS-1 cDNA, as well as clinical and deletion mutant proteins, into sel-12 mutant animals and tested their potential to rescue the egg-laying defect. Human PS-1 expressed from the sel-12 promoter fully rescued the sel-12 phenotype, whereas two missense mutations, C410Y and A246E, identified in pedigrees with FAD, exhibited a strongly decreased rescuing activity. The large hydrophilic loop and transmembrane domain 7 are required for the biological activity of PS-1. PS-1 protein was proteolytically cleaved in C. elegans as it is in human cells. A PS-1 splice variant (FAD mutation deltaexon9) that does not undergo proteolytic cleavage also substituted for sel-12. The conservation of function of human PS-1 and C. elegans sel-12 suggests that presenilin proteins are required, directly or indirectly, for the proper operation of the Notch signalling pathway. FAD-associated mutant proteins tested showed different rescuing activities, indicating that they might affect different functional or regulatory aspects of PS-1. Proteolytic processing is not a prerequisite for PS-1 function in C. elegans.
Laboratory of Molecular Biology/Genzentrum of the University of Munich, Germany.
R
R
Baumeister
U
U
Leimer
I
I
Zweckbronner
C
C
Jakubek
J
J
Grünberg
C
C
Haass
D000544:Alzheimer Disease / Q000235:genetics*; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D010641:Phenotype; D010957:Plasmids; D053764:Presenilin-1; D011499:Protein Processing, Post-Translational; D051880:Receptors, Notch; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D051880:Receptors, Notch; D011994:Recombinant Proteins