Apoptotic activities of wild-type and Alzheimer's disease-related mutant presenilins in Drosophila melanogaster.
Mutant human presenilins cause early-onset familial Alzheimer's disease and render cells susceptible to apoptosis in cultured cell models. We show that loss of presenilin function in Drosophila melanogaster increases levels of apoptosis in developing tissues. Moreover, overexpression of presenilin causes apoptotic and neurogenic phenotypes resembling those of Presenilin loss-of-function mutants, suggesting that presenilin exerts a dominant negative effect when expressed at high levels. In Drosophila S2 cells, Psn overexpression leads to reduced Notch receptor synthesis affecting levels of the intact approximately 300-kD precursor and its approximately 120-kD processed COOH-terminal derivatives. Presenilin-induced apoptosis is cell autonomous and can be blocked by constitutive Notch activation, suggesting that the increased cell death is due to a developmental mechanism that eliminates improperly specified cell types. We describe a genetic model in which the apoptotic activities of wild-type and mutant presenilins can be assessed, and we find that Alzheimer's disease-linked mutant presenilins are less effective at inducing apoptosis than wild-type presenilin.
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Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Fortini
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D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics*; D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis; D002460:Cell Line; D029721:Drosophila Proteins; D004331:Drosophila melanogaster / Q000166:cytology* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D005123:Eye / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D018628:Gene Dosage; D015870:Gene Expression; D005799:Genes, Dominant / Q000235:genetics; D051034:Inhibitor of Apoptosis Proteins; D019476:Insect Proteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008957:Models, Genetic; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D053763:Presenilins; D051880:Receptors, Notch; D015398:Signal Transduction; D013489:Suppression, Genetic; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D014921:Wings, Animal / Q000166:cytology / Q000254:growth & development / Q000378:metabolism
C111891:DIAP1 protein, Drosophila; D029721:Drosophila Proteins; D051034:Inhibitor of Apoptosis Proteins; D019476:Insect Proteins; D008565:Membrane Proteins; C497759:N protein, Drosophila; D010446:Peptide Fragments; D053763:Presenilins; C106427:Psn protein, Drosophila; D051880:Receptors, Notch; D014764:Viral Proteins; C086430:inhibitor of apoptosis, Nucleopolyhedrovirus