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. 1999 Jul;65(1):7–12. doi: 10.1086/302475

Function and dysfunction of the presenilins.

S S Sisodia 1, S H Kim 1, G Thinakaran 1
PMCID: PMC1378068  PMID: 10364510

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baumeister R., Leimer U., Zweckbronner I., Jakubek C., Grünberg J., Haass C. Human presenilin-1, but not familial Alzheimer's disease (FAD) mutants, facilitate Caenorhabditis elegans Notch signalling independently of proteolytic processing. Genes Funct. 1997 Apr;1(2):149–159. doi: 10.1046/j.1365-4624.1997.00012.x. [DOI] [PubMed] [Google Scholar]
  2. Borchelt D. R., Ratovitski T., van Lare J., Lee M. K., Gonzales V., Jenkins N. A., Copeland N. G., Price D. L., Sisodia S. S. Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron. 1997 Oct;19(4):939–945. doi: 10.1016/s0896-6273(00)80974-5. [DOI] [PubMed] [Google Scholar]
  3. De Strooper B., Annaert W., Cupers P., Saftig P., Craessaerts K., Mumm J. S., Schroeter E. H., Schrijvers V., Wolfe M. S., Ray W. J. A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature. 1999 Apr 8;398(6727):518–522. doi: 10.1038/19083. [DOI] [PubMed] [Google Scholar]
  4. De Strooper B., Saftig P., Craessaerts K., Vanderstichele H., Guhde G., Annaert W., Von Figura K., Van Leuven F. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature. 1998 Jan 22;391(6665):387–390. doi: 10.1038/34910. [DOI] [PubMed] [Google Scholar]
  5. Doan A., Thinakaran G., Borchelt D. R., Slunt H. H., Ratovitsky T., Podlisny M., Selkoe D. J., Seeger M., Gandy S. E., Price D. L. Protein topology of presenilin 1. Neuron. 1996 Nov;17(5):1023–1030. doi: 10.1016/s0896-6273(00)80232-9. [DOI] [PubMed] [Google Scholar]
  6. Giulian D. Microglia and the immune pathology of Alzheimer disease. Am J Hum Genet. 1999 Jul;65(1):13–18. doi: 10.1086/302477. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Holcomb L., Gordon M. N., McGowan E., Yu X., Benkovic S., Jantzen P., Wright K., Saad I., Mueller R., Morgan D. Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med. 1998 Jan;4(1):97–100. doi: 10.1038/nm0198-097. [DOI] [PubMed] [Google Scholar]
  8. Kim T. W., Pettingell W. H., Hallmark O. G., Moir R. D., Wasco W., Tanzi R. E. Endoproteolytic cleavage and proteasomal degradation of presenilin 2 in transfected cells. J Biol Chem. 1997 Apr 25;272(17):11006–11010. doi: 10.1074/jbc.272.17.11006. [DOI] [PubMed] [Google Scholar]
  9. Lah J. J., Heilman C. J., Nash N. R., Rees H. D., Yi H., Counts S. E., Levey A. I. Light and electron microscopic localization of presenilin-1 in primate brain. J Neurosci. 1997 Mar 15;17(6):1971–1980. doi: 10.1523/JNEUROSCI.17-06-01971.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Lee M. K., Slunt H. H., Martin L. J., Thinakaran G., Kim G., Gandy S. E., Seeger M., Koo E., Price D. L., Sisodia S. S. Expression of presenilin 1 and 2 (PS1 and PS2) in human and murine tissues. J Neurosci. 1996 Dec 1;16(23):7513–7525. doi: 10.1523/JNEUROSCI.16-23-07513.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Lemere C. A., Lopera F., Kosik K. S., Lendon C. L., Ossa J., Saido T. C., Yamaguchi H., Ruiz A., Martinez A., Madrigal L. The E280A presenilin 1 Alzheimer mutation produces increased A beta 42 deposition and severe cerebellar pathology. Nat Med. 1996 Oct;2(10):1146–1150. doi: 10.1038/nm1096-1146. [DOI] [PubMed] [Google Scholar]
  12. Levitan D., Doyle T. G., Brousseau D., Lee M. K., Thinakaran G., Slunt H. H., Sisodia S. S., Greenwald I. Assessment of normal and mutant human presenilin function in Caenorhabditis elegans. Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14940–14944. doi: 10.1073/pnas.93.25.14940. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Levitan D., Greenwald I. Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer's disease gene. Nature. 1995 Sep 28;377(6547):351–354. doi: 10.1038/377351a0. [DOI] [PubMed] [Google Scholar]
  14. Levy-Lahad E., Wasco W., Poorkaj P., Romano D. M., Oshima J., Pettingell W. H., Yu C. E., Jondro P. D., Schmidt S. D., Wang K. Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science. 1995 Aug 18;269(5226):973–977. doi: 10.1126/science.7638622. [DOI] [PubMed] [Google Scholar]
  15. Levy-Lahad E., Wijsman E. M., Nemens E., Anderson L., Goddard K. A., Weber J. L., Bird T. D., Schellenberg G. D. A familial Alzheimer's disease locus on chromosome 1. Science. 1995 Aug 18;269(5226):970–973. doi: 10.1126/science.7638621. [DOI] [PubMed] [Google Scholar]
  16. Li X., Greenwald I. Membrane topology of the C. elegans SEL-12 presenilin. Neuron. 1996 Nov;17(5):1015–1021. doi: 10.1016/s0896-6273(00)80231-7. [DOI] [PubMed] [Google Scholar]
  17. Naruse S., Thinakaran G., Luo J. J., Kusiak J. W., Tomita T., Iwatsubo T., Qian X., Ginty D. D., Price D. L., Borchelt D. R. Effects of PS1 deficiency on membrane protein trafficking in neurons. Neuron. 1998 Nov;21(5):1213–1221. doi: 10.1016/s0896-6273(00)80637-6. [DOI] [PubMed] [Google Scholar]
  18. Nishimura M., Yu G., Levesque G., Zhang D. M., Ruel L., Chen F., Milman P., Holmes E., Liang Y., Kawarai T. Presenilin mutations associated with Alzheimer disease cause defective intracellular trafficking of beta-catenin, a component of the presenilin protein complex. Nat Med. 1999 Feb;5(2):164–169. doi: 10.1038/5526. [DOI] [PubMed] [Google Scholar]
  19. Podlisny M. B., Citron M., Amarante P., Sherrington R., Xia W., Zhang J., Diehl T., Levesque G., Fraser P., Haass C. Presenilin proteins undergo heterogeneous endoproteolysis between Thr291 and Ala299 and occur as stable N- and C-terminal fragments in normal and Alzheimer brain tissue. Neurobiol Dis. 1997;3(4):325–337. doi: 10.1006/nbdi.1997.0129. [DOI] [PubMed] [Google Scholar]
  20. Price D. L., Sisodia S. S. Mutant genes in familial Alzheimer's disease and transgenic models. Annu Rev Neurosci. 1998;21:479–505. doi: 10.1146/annurev.neuro.21.1.479. [DOI] [PubMed] [Google Scholar]
  21. Ray W. J., Yao M., Nowotny P., Mumm J., Zhang W., Wu J. Y., Kopan R., Goate A. M. Evidence for a physical interaction between presenilin and Notch. Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):3263–3268. doi: 10.1073/pnas.96.6.3263. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Rogaev E. I., Sherrington R., Rogaeva E. A., Levesque G., Ikeda M., Liang Y., Chi H., Lin C., Holman K., Tsuda T. Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature. 1995 Aug 31;376(6543):775–778. doi: 10.1038/376775a0. [DOI] [PubMed] [Google Scholar]
  23. Saura C. A., Tomita T., Davenport F., Harris C. L., Iwatsubo T., Thinakaran G. Evidence that intramolecular associations between presenilin domains are obligatory for endoproteolytic processing. J Biol Chem. 1999 May 14;274(20):13818–13823. doi: 10.1074/jbc.274.20.13818. [DOI] [PubMed] [Google Scholar]
  24. Schellenberg G. D., Bird T. D., Wijsman E. M., Orr H. T., Anderson L., Nemens E., White J. A., Bonnycastle L., Weber J. L., Alonso M. E. Genetic linkage evidence for a familial Alzheimer's disease locus on chromosome 14. Science. 1992 Oct 23;258(5082):668–671. doi: 10.1126/science.1411576. [DOI] [PubMed] [Google Scholar]
  25. Scheuner D., Eckman C., Jensen M., Song X., Citron M., Suzuki N., Bird T. D., Hardy J., Hutton M., Kukull W. Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nat Med. 1996 Aug;2(8):864–870. doi: 10.1038/nm0896-864. [DOI] [PubMed] [Google Scholar]
  26. Selkoe D. J. The cell biology of beta-amyloid precursor protein and presenilin in Alzheimer's disease. Trends Cell Biol. 1998 Nov;8(11):447–453. doi: 10.1016/s0962-8924(98)01363-4. [DOI] [PubMed] [Google Scholar]
  27. Shen J., Bronson R. T., Chen D. F., Xia W., Selkoe D. J., Tonegawa S. Skeletal and CNS defects in Presenilin-1-deficient mice. Cell. 1997 May 16;89(4):629–639. doi: 10.1016/s0092-8674(00)80244-5. [DOI] [PubMed] [Google Scholar]
  28. Sherrington R., Rogaev E. I., Liang Y., Rogaeva E. A., Levesque G., Ikeda M., Chi H., Lin C., Li G., Holman K. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 1995 Jun 29;375(6534):754–760. doi: 10.1038/375754a0. [DOI] [PubMed] [Google Scholar]
  29. Stahl B., Diehlmann A., Südhof T. C. Direct interaction of Alzheimer's disease-related presenilin 1 with armadillo protein p0071. J Biol Chem. 1999 Apr 2;274(14):9141–9148. doi: 10.1074/jbc.274.14.9141. [DOI] [PubMed] [Google Scholar]
  30. Struhl G., Greenwald I. Presenilin is required for activity and nuclear access of Notch in Drosophila. Nature. 1999 Apr 8;398(6727):522–525. doi: 10.1038/19091. [DOI] [PubMed] [Google Scholar]
  31. Tanzi R. E., Kovacs D. M., Kim T. W., Moir R. D., Guenette S. Y., Wasco W. The gene defects responsible for familial Alzheimer's disease. Neurobiol Dis. 1996;3(3):159–168. doi: 10.1006/nbdi.1996.0016. [DOI] [PubMed] [Google Scholar]
  32. Thinakaran G., Borchelt D. R., Lee M. K., Slunt H. H., Spitzer L., Kim G., Ratovitsky T., Davenport F., Nordstedt C., Seeger M. Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron. 1996 Jul;17(1):181–190. doi: 10.1016/s0896-6273(00)80291-3. [DOI] [PubMed] [Google Scholar]
  33. Thinakaran G., Regard J. B., Bouton C. M., Harris C. L., Price D. L., Borchelt D. R., Sisodia S. S. Stable association of presenilin derivatives and absence of presenilin interactions with APP. Neurobiol Dis. 1998 Apr;4(6):438–453. doi: 10.1006/nbdi.1998.0171. [DOI] [PubMed] [Google Scholar]
  34. Weidemann A., Paliga K., Dürrwang U., Czech C., Evin G., Masters C. L., Beyreuther K. Formation of stable complexes between two Alzheimer's disease gene products: presenilin-2 and beta-amyloid precursor protein. Nat Med. 1997 Mar;3(3):328–332. doi: 10.1038/nm0397-328. [DOI] [PubMed] [Google Scholar]
  35. Westlund B., Parry D., Clover R., Basson M., Johnson C. D. Reverse genetic analysis of Caenorhabditis elegans presenilins reveals redundant but unequal roles for sel-12 and hop-1 in Notch-pathway signaling. Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2497–2502. doi: 10.1073/pnas.96.5.2497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Wolfe M. S., Xia W., Ostaszewski B. L., Diehl T. S., Kimberly W. T., Selkoe D. J. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature. 1999 Apr 8;398(6727):513–517. doi: 10.1038/19077. [DOI] [PubMed] [Google Scholar]
  37. Wong P. C., Zheng H., Chen H., Becher M. W., Sirinathsinghji D. J., Trumbauer M. E., Chen H. Y., Price D. L., Van der Ploeg L. H., Sisodia S. S. Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm. Nature. 1997 May 15;387(6630):288–292. doi: 10.1038/387288a0. [DOI] [PubMed] [Google Scholar]
  38. Xia W., Zhang J., Perez R., Koo E. H., Selkoe D. J. Interaction between amyloid precursor protein and presenilins in mammalian cells: implications for the pathogenesis of Alzheimer disease. Proc Natl Acad Sci U S A. 1997 Jul 22;94(15):8208–8213. doi: 10.1073/pnas.94.15.8208. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Ye Y., Lukinova N., Fortini M. E. Neurogenic phenotypes and altered Notch processing in Drosophila Presenilin mutants. Nature. 1999 Apr 8;398(6727):525–529. doi: 10.1038/19096. [DOI] [PubMed] [Google Scholar]
  40. Yu G., Chen F., Levesque G., Nishimura M., Zhang D. M., Levesque L., Rogaeva E., Xu D., Liang Y., Duthie M. The presenilin 1 protein is a component of a high molecular weight intracellular complex that contains beta-catenin. J Biol Chem. 1998 Jun 26;273(26):16470–16475. doi: 10.1074/jbc.273.26.16470. [DOI] [PubMed] [Google Scholar]
  41. Zhang Z., Hartmann H., Do V. M., Abramowski D., Sturchler-Pierrat C., Staufenbiel M., Sommer B., van de Wetering M., Clevers H., Saftig P. Destabilization of beta-catenin by mutations in presenilin-1 potentiates neuronal apoptosis. Nature. 1998 Oct 15;395(6703):698–702. doi: 10.1038/27208. [DOI] [PubMed] [Google Scholar]
  42. Zhou J., Liyanage U., Medina M., Ho C., Simmons A. D., Lovett M., Kosik K. S. Presenilin 1 interaction in the brain with a novel member of the Armadillo family. Neuroreport. 1997 May 27;8(8):2085–2090. doi: 10.1097/00001756-199705260-00054. [DOI] [PubMed] [Google Scholar]

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