{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T11:42:34Z","timestamp":1791114154659,"version":"4.1.0"},"reference-count":58,"publisher":"Rockefeller University Press","issue":"6","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[1999,9,20]]},"abstract":"<jats:p>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 \u223c300-kD precursor and its \u223c120-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.<\/jats:p>","DOI":"10.1083\/jcb.146.6.1351","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T16:45:41Z","timestamp":1027701941000},"page":"1351-1364","update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":92,"title":["Apoptotic Activities of Wild-Type and Alzheimer's Disease-Related Mutant Presenilins in <i>Drosophila melanogaster<\/i>"],"prefix":"10.1083","volume":"146","author":[{"given":"Yihong","family":"Ye","sequence":"first","affiliation":[{"name":"aDepartment of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark E.","family":"Fortini","sequence":"additional","affiliation":[{"name":"aDepartment of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[1999,9,20]]},"reference":[{"key":"2023072901263996400_Abramsetal1993","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1242\/dev.117.1.29","article-title":"Programmed cell death during Drosophila embryogenesis","volume":"117","author":"Abrams","year":"1993","journal-title":"Development."},{"key":"2023072901263996400_Barinaga1998","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1126\/science.281.5381.1303","article-title":"Is apoptosis key in Alzheimer's disease?","volume":"281","author":"Barinaga","year":"1998","journal-title":"Science."},{"key":"2023072901263996400_BoniniandFortini1999","article-title":"Surviving Drosophila eye developmentintegrating cell death with differentiation during formation of a neural structure","volume":"In press","author":"Bonini","year":"1999","journal-title":"BioEssays"},{"key":"2023072901263996400_BrandandPerrimon1993","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1242\/dev.118.2.401","article-title":"Targeted gene expression as a means of altering cell fates and generating dominant phenotypes","volume":"118","author":"Brand","year":"1993","journal-title":"Development."},{"key":"2023072901263996400_Bursztajnetal1998","doi-asserted-by":"crossref","first-page":"9790","DOI":"10.1523\/JNEUROSCI.18-23-09790.1998","article-title":"Overexpression in neurons of human presenilin-1 or a presenilin-1 familial Alzheimer disease mutant does not enhance apoptosis","volume":"18","author":"Bursztajn","year":"1998","journal-title":"J. Neurosci."},{"key":"2023072901263996400_CaganandReady1989","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1101\/gad.3.8.1099","article-title":"Notch is required for successive cell decisions in the developing Drosophila retina","volume":"3","author":"Cagan","year":"1989","journal-title":"Genes Dev."},{"key":"2023072901263996400_Campionetal1996","doi-asserted-by":"crossref","first-page":"1582","DOI":"10.1097\/00001756-199607080-00009","article-title":"A novel presenilin 1 mutation resulting in familial Alzheimer's disease with an onset age of 29 years","volume":"7","author":"Campion","year":"1996","journal-title":"Neuroreport."},{"key":"2023072901263996400_DavidsonandSteller1998","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1038\/35385","article-title":"Blocking apoptosis prevents blindness in Drosophila retinal degeneration mutants","volume":"391","author":"Davidson","year":"1998","journal-title":"Nature."},{"key":"2023072901263996400_Davisetal1998","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1016\/S0896-6273(00)80998-8","article-title":"An Alzheimer's disease-linked PS1 variant rescues the developmental abnormalities of PS1-deficient embryos","volume":"20","author":"Davis","year":"1998","journal-title":"Neuron."},{"key":"2023072901263996400_DeStrooperetal1999","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1038\/19083","article-title":"A presenilin-1\u2013dependent \u03b3-secretase\u2013like protease mediates release of Notch intracellular domain","volume":"398","author":"De Strooper","year":"1999","journal-title":"Nature."},{"key":"2023072901263996400_Dengetal1996","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/S0014-5793(96)01142-8","article-title":"Alzheimer-associated presenilin-2 confers increased sensitivity to apoptosis in PC12 cells","volume":"397","author":"Deng","year":"1996","journal-title":"FEBS Lett."},{"key":"2023072901263996400_Ellisetal1993","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1242\/dev.119.3.855","article-title":"Expression of Drosophila glass protein and evidence for negative regulation of its activity in non-neuronal cells by another DNA-binding protein","volume":"119","author":"Ellis","year":"1993","journal-title":"Development."},{"key":"2023072901263996400_Fehonetal1990","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1016\/0092-8674(90)90534-L","article-title":"Molecular interactions between the protein products of the neurogenic loci Notch and Delta, two EGF-homologous genes in Drosophila","volume":"61","author":"Fehon","year":"1990","journal-title":"Cell."},{"key":"2023072901263996400_Fortinietal1993","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1038\/365555a0","article-title":"An activated Notch receptor blocks cell-fate commitment in the developing Drosophila eye","volume":"365","author":"Fortini","year":"1993","journal-title":"Nature."},{"key":"2023072901263996400_Gavrielietal1992","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1083\/jcb.119.3.493","article-title":"Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation","volume":"119","author":"Gavrieli","year":"1992","journal-title":"J. Cell Biol."},{"key":"2023072901263996400_Guoetal1996","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1097\/00001756-199612200-00074","article-title":"Alzheimer's PS-1 mutation perturbs calcium homeostasis and sensitizes PC12 cells to death induced by amyloid \u03b2-peptide","volume":"8","author":"Guo","year":"1996","journal-title":"Neuroreport."},{"key":"2023072901263996400_Guoetal1997","doi-asserted-by":"crossref","first-page":"4212","DOI":"10.1523\/JNEUROSCI.17-11-04212.1997","article-title":"Alzheimer's presenilin mutation sensitizes neural cells to apoptosis induced by trophic factor withdrawal and amyloid \u03b2-peptideinvolvement of calcium and oxyradicals","volume":"17","author":"Guo","year":"1997","journal-title":"J. Neurosci."},{"key":"2023072901263996400_Haass1997","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1016\/S0896-6273(00)80309-8","article-title":"Presenilinsgenes for life and death","volume":"18","author":"Haass","year":"1997","journal-title":"Neuron."},{"key":"2023072901263996400_HaassandSelkoe1993","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1016\/0092-8674(93)90312-E","article-title":"Cellular processing of \u03b2-amyloid precursor protein and the genesis of amyloid \u03b2-peptide","volume":"75","author":"Haass","year":"1993","journal-title":"Cell."},{"key":"2023072901263996400_Hayetal1995","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1016\/0092-8674(95)90150-7","article-title":"Drosophila homologs of baculovirus inhibitor of apoptosis proteins function to block cell death","volume":"83","author":"Hay","year":"1995","journal-title":"Cell."},{"key":"2023072901263996400_Hongetal1999","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1523\/JNEUROSCI.19-02-00637.1999","article-title":"Contrasting role of presenilin-1 and presenilin-2 in neuronal differentiation in vitro","volume":"19","author":"Hong","year":"1999","journal-title":"J. Neurosci."},{"key":"2023072901263996400_Jacobsonetal1997","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/S0092-8674(00)81873-5","article-title":"Programmed cell death in animal development","volume":"88","author":"Jacobson","year":"1997","journal-title":"Cell."},{"key":"2023072901263996400_JanickiandMonteiro1997","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1083\/jcb.139.2.485","article-title":"Increased apoptosis arising from increased expression of the Alzheimer's disease-associated presenilin-2 mutation (N141I)","volume":"139","author":"Janicki","year":"1997","journal-title":"J. Cell Biol."},{"key":"2023072901263996400_Jehnetal1999","doi-asserted-by":"crossref","first-page":"635","DOI":"10.4049\/jimmunol.162.2.635","article-title":"Protective effects of Notch-1 on TCR-induced apoptosis","volume":"162","author":"Jehn","year":"1999","journal-title":"J. Immunol."},{"key":"2023072901263996400_Kimetal1996","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/382133a0","article-title":"Integration of positional signals and regulation of wing formation and identity by Drosophila vestigial gene","volume":"382","author":"Kim","year":"1996","journal-title":"Nature."},{"key":"2023072901263996400_LevitanandGreenwald1995","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1038\/377351a0","article-title":"Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer's disease gene","volume":"377","author":"Levitan","year":"1995","journal-title":"Nature."},{"key":"2023072901263996400_LevitanandGreenwald1998","doi-asserted-by":"crossref","first-page":"3599","DOI":"10.1242\/dev.125.18.3599","article-title":"Effects of SEL-12 presenilin on LIN-12 localization and function in Caenorhabditis elegans","volume":"125","author":"Levitan","year":"1998","journal-title":"Development."},{"key":"2023072901263996400_Levitanetal1996","doi-asserted-by":"crossref","first-page":"14940","DOI":"10.1073\/pnas.93.25.14940","article-title":"Assessment of normal and mutant human presenilin function in Caenorhabditis elegans","volume":"93","author":"Levitan","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072901263996400_LiandGreenwald1997","doi-asserted-by":"crossref","first-page":"12204","DOI":"10.1073\/pnas.94.22.12204","article-title":"HOP-1, a Caenorhabditis elegans presenilin, appears to be functionally redundant with SEL-12 presenilin and to facilitate LIN-12 and GLP-1 signaling","volume":"94","author":"Li","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072901263996400_LindsleyandZimm1992","volume-title":"The Genome of Drosophila melanogaster","author":"Lindsley","year":"1992"},{"key":"2023072901263996400_McCallandSteller1997","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/S0168-9525(97)01126-8","article-title":"Facing death in the flygenetic analysis of apoptosis in Drosophila","volume":"13","author":"McCall","year":"1997","journal-title":"Trends Genet."},{"key":"2023072901263996400_Priceetal1998","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1126\/science.282.5391.1079","article-title":"Genetic neurodegenerative diseasesthe human illness and transgenic models","volume":"282","author":"Price","year":"1998","journal-title":"Science."},{"key":"2023072901263996400_Qianetal1998","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1016\/S0896-6273(00)80999-X","article-title":"Mutant human presenilin 1 protects presenilin 1 null mouse against embryonic lethality and elevates A\u03b21-42\/43 expression","volume":"20","author":"Qian","year":"1998","journal-title":"Neuron."},{"key":"2023072901263996400_Raff1998","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1038\/24055","article-title":"Cell suicide for beginners","volume":"396","author":"Raff","year":"1998","journal-title":"Nature."},{"key":"2023072901263996400_Readyetal1976","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/0012-1606(76)90225-6","article-title":"Development of the Drosophila retina, a neurocrystalline lattice","volume":"53","author":"Ready","year":"1976","journal-title":"Dev. Biol."},{"key":"2023072901263996400_RobinowandWhite1991","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1002\/neu.480220503","article-title":"Characterization and spatial distribution of the ELAV protein during Drosophila melanogaster development","volume":"22","author":"Robinow","year":"1991","journal-title":"J. Neurobiol."},{"key":"2023072901263996400_RulifsonandBlair1995","doi-asserted-by":"crossref","first-page":"2813","DOI":"10.1242\/dev.121.9.2813","article-title":"Notch regulates wingless expression and is not required for reception of the paracrine wingless signal during wing margin neurogenesis in Drosophila","volume":"121","author":"Rulifson","year":"1995","journal-title":"Development."},{"key":"2023072901263996400_Seegeretal1997","doi-asserted-by":"crossref","first-page":"5090","DOI":"10.1073\/pnas.94.10.5090","article-title":"Evidence for phosphorylation and oligomeric assembly of presenilin 1","volume":"94","author":"Seeger","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072901263996400_Selkoe1998","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/S0962-8924(98)01363-4","article-title":"The cell biology of \u03b2-amyloid precursor protein and presenilin in Alzheimer's disease","volume":"8","author":"Selkoe","year":"1998","journal-title":"Trends Cell Biol."},{"key":"2023072901263996400_Shenetal1997","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1016\/S0092-8674(00)80244-5","article-title":"Skeletal and CNS defects in Presenilin-1\u2013deficient mice","volume":"89","author":"Shen","year":"1997","journal-title":"Cell."},{"key":"2023072901263996400_SpradlingandRubin1982","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1126\/science.6289435","article-title":"Transposition of cloned P elements into Drosophila germ line chromosomes","volume":"218","author":"Spradling","year":"1982","journal-title":"Science."},{"key":"2023072901263996400_Spreij1971","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1163\/002829670X00295","article-title":"Cell death during the development of the imaginal discs of Calliphora erythrocephala","volume":"21","author":"Spreij","year":"1971","journal-title":"Netherlands J. Zool."},{"key":"2023072901263996400_StruhlandAdachi1998","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/S0092-8674(00)81193-9","article-title":"Nuclear access and action of Notch in vivo","volume":"93","author":"Struhl","year":"1998","journal-title":"Cell."},{"key":"2023072901263996400_StruhlandGreenwald1999","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1038\/19091","article-title":"Presenilin is required for activity and nuclear access of Notch in Drosophila","volume":"398","author":"Struhl","year":"1999","journal-title":"Nature."},{"key":"2023072901263996400_Struhletal1993","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/0092-8674(93)90424-O","article-title":"Intrinsic activity of the Lin-12 and Notch intracellular domains in vivo","volume":"74","author":"Struhl","year":"1993","journal-title":"Cell."},{"key":"2023072901263996400_TomlinsonandReady1987","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/0012-1606(87)90448-9","article-title":"Cell fate in the Drosophila ommatidium","volume":"123","author":"Tomlinson","year":"1987","journal-title":"Dev. Biol."},{"key":"2023072901263996400_Tomlinsonetal1987","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/0092-8674(87)90019-5","article-title":"Localization of the sevenless protein, a putative receptor for positional information, in the eye imaginal disc of Drosophila","volume":"51","author":"Tomlinson","year":"1987","journal-title":"Cell."},{"key":"2023072901263996400_VanDorenetal1992","doi-asserted-by":"crossref","first-page":"2592","DOI":"10.1101\/gad.6.12b.2592","article-title":"Spatial regulation of proneural gene activityauto- and cross-activation of achaete is antagonized by extramacrochaetae","volume":"6","author":"Van Doren","year":"1992","journal-title":"Genes Dev."},{"key":"2023072901263996400_N0x298d1a0N0x3753a90","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/S0304-3940(99)00097-X","article-title":"Overexpression of a C-terminal fragment of presenilin 1 delays anti-Fas induced apoptosis in Jurkat cells","volume":"263","author":"V\u00e9zina","year":"1999","journal-title":"Neurosci. Lett."},{"key":"2023072901263996400_Vitoetal1996","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1126\/science.271.5248.521","article-title":"Interfering with apoptosisCa2+-binding protein ALG-2 and Alzheimer's disease gene ALG-3","volume":"271","author":"Vito","year":"1996","journal-title":"Science."},{"key":"2023072901263996400_Vitoetal1997","doi-asserted-by":"crossref","first-page":"28315","DOI":"10.1074\/jbc.272.45.28315","article-title":"Generation of anti-apoptotic presenilin-2 polypeptides by alternative transcription, proteolysis, and caspase-3 cleavage","volume":"272","author":"Vito","year":"1997","journal-title":"J. Biol. Chem."},{"key":"2023072901263996400_Weihletal1999","doi-asserted-by":"crossref","first-page":"5360","DOI":"10.1523\/JNEUROSCI.19-13-05360.1999","article-title":"Mutant presenilin-1 induces apoptosis and downregulates Akt\/PKB","volume":"19","author":"Weihl","year":"1999","journal-title":"J. Neurosci."},{"key":"2023072901263996400_WolffandReady1991","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1242\/dev.113.3.825","article-title":"Cell death in normal and rough eye mutants of Drosophila","volume":"113","author":"Wolff","year":"1991","journal-title":"Development."},{"key":"2023072901263996400_Wolozinetal1996","doi-asserted-by":"crossref","first-page":"1710","DOI":"10.1126\/science.274.5293.1710","article-title":"Participation of presenilin 2 in apoptosisenhanced basal activity conferred by an Alzheimer mutation","volume":"274","author":"Wolozin","year":"1996","journal-title":"Science."},{"key":"2023072901263996400_Wongetal1997","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1038\/387288a0","article-title":"Presenilin 1 is required for Notch1 and Dll1 expression in the paraxial mesoderm","volume":"387","author":"Wong","year":"1997","journal-title":"Nature."},{"key":"2023072901263996400_YeandFortini1998","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/S0925-4773(98)00169-5","article-title":"Characterization of Drosophila presenilin and its colocalization with Notch during development","volume":"79","author":"Ye","year":"1998","journal-title":"Mech. Dev."},{"key":"2023072901263996400_Yeetal1999","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1038\/19096","article-title":"Neurogenic phenotypes and altered Notch processing in Drosophila Presenilin mutants","volume":"398","author":"Ye","year":"1999","journal-title":"Nature."},{"key":"2023072901263996400_Zhangetal1998","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1038\/27208","article-title":"Destabilization of \u03b2-catenin by mutations in presenilin-1 potentiates neuronal apoptosis","volume":"395","author":"Zhang","year":"1998","journal-title":"Nature."}],"container-title":["The Journal of Cell Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jcb\/article-pdf\/146\/6\/1351\/1854151\/9905082.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jcb\/article-pdf\/146\/6\/1351\/1854151\/9905082.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,29]],"date-time":"2023-07-29T01:27:33Z","timestamp":1690594053000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jcb\/article\/146\/6\/1351\/32001\/Apoptotic-Activities-of-Wild-Type-and-Alzheimer-s"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1999,9,20]]},"references-count":58,"journal-issue":{"issue":"6","published-print":{"date-parts":[[1999,9,20]]}},"URL":"https:\/\/doi.org\/10.1083\/jcb.146.6.1351","relation":{},"ISSN":["0021-9525","1540-8140"],"issn-type":[{"value":"0021-9525","type":"print"},{"value":"1540-8140","type":"electronic"}],"subject":[],"published":{"date-parts":[[1999,9,20]]}}}