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Gene Review

PSEN1  -  presenilin 1

Homo sapiens

Synonyms: AD3, FAD, PS-1, PS1, PSNL1, ...
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Disease relevance of PSEN1


Psychiatry related information on PSEN1


High impact information on PSEN1

  • In experiments with PS1/2 double knockout (DKO) mouse embryonic fibroblasts (MEFs), we find that presenilins account for approximately 80% of passive Ca(2+) leak from the endoplasmic reticulum [12].
  • FAD mutations and genetic deletions of presenilins have been associated with calcium (Ca(2+)) signaling abnormalities [12].
  • Our studies define how presenilin-dependent nuclear signaling by a receptor tyrosine kinase directly regulates gene transcription and cell fate [13].
  • Mutations in PS-1 associated with Alzheimer's disease interfere with CBP proteolysis, leading to abnormal transcription [14].
  • These data raise the possibility that FAD mutation-induced transcriptional abnormalities maybe causally related to the dementia associated with FAD [15].

Chemical compound and disease context of PSEN1


Biological context of PSEN1


Anatomical context of PSEN1


Associations of PSEN1 with chemical compounds

  • Sequencing of the PSEN1 gene revealed a heterozygous base substitution, C520A (exon 6), which is predicted to cause an amino acid change from leucine to methionine in the TMIII of the presenilin 1 protein [26].
  • That PS1 is a constituent of the cadherin/catenin complex makes that complex a potential target for PS1 FAD mutations [23].
  • Inactivating PS1 or PS2 function by mutagenesis of one of the critical aspartate residues or by gamma-secretase inhibitors results in delayed reinternalization of the beta-amyloid precursor protein and its accumulation at the cell surface [24].
  • The major portion of intracellular Abeta at steady state was found in the same Golgi/trans-Golgi network-rich vesicles, and Abeta levels in these fractions were markedly reduced when either PS1 TM aspartate was mutated to alanine [27].
  • We detected an A-to-G transition in the PS-1 gene, resulting in a glutamic acid (Glu)-to-glycine (Gly) substitution at codon 318 in 2 familial and 2 sporadic AD patients [28].
  • Inhibition of RyR or inositol trisphosphate receptor channels, but not SERCA pumps, increased the expression of presenilin-1 [29].

Physical interactions of PSEN1


Enzymatic interactions of PSEN1

  • It was hypothesized that PS1 might directly cleave APP [35].
  • Impas 1 possesses endoproteolytic activity against multipass membrane protein substrate cleaving the presenilin 1 holoprotein [36].
  • In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro [37].
  • PS1 protein is generated as a 47 kDa protein and is endoproteolytically cleaved into N-terminal 28 kDa and C-terminal 19 kDa fragments in vivo [38].
  • Recombinant memapsin 2 also cleaved a peptide derived from the processing site of presenilin 1, albeit with poor kinetic efficiency [39].

Co-localisations of PSEN1

  • Immunostaining experiments revealed that for all the cell types PS1 is present at the plasma membrane and co-localizes with N-cadherin, a component of the cell-cell adhesion complex [40].

Regulatory relationships of PSEN1

  • However, we show that ubiquilin promotes presenilin protein accumulation [25].
  • Presenilin 1 mutations activate gamma 42-secretase but reciprocally inhibit epsilon-secretase cleavage of amyloid precursor protein (APP) and S3-cleavage of notch [41].
  • We revisited presenilin-1 topology by inserting glycosylation consensus sequences in human PS1 and expressing the obtained mutants in a presenilin-1 and 2 knock-out background [42].
  • Strikingly, the PS1 L166P mutation not only induces an exceptionally high increase of Abeta(42) production but also impairs NICD production and Notch signaling, as well as AICD generation [43].
  • Inhibiting amyloid precursor protein C-terminal cleavage promotes an interaction with presenilin 1 [44].

Other interactions of PSEN1

  • Presenilin mutations produce increases in beta-amyloid (Abeta) formation and apoptosis in many experimental systems [45].
  • A beta ending at A beta 42(43) was also significantly elevated in fibroblast media from subjects with PS1 (P < 0.0001) or PS2 (P = 0.03) mutations [22].
  • Calsenilin: a calcium-binding protein that interacts with the presenilins and regulates the levels of a presenilin fragment [45].
  • Together, these data show that PS1 incorporates into the cadherin/catenin adhesion system and regulates cell-cell adhesion [23].
  • Thus, the biological activity of gamma-secretase is reconstituted by the co-expression of human PS, Nct, APH-1 and PEN-2 in yeast [46].
  • These results suggest that the conserved transmembrane histidine residues contribute to APH1 function and can affect presenilin catalytic activity [47].

Analytical, diagnostic and therapeutic context of PSEN1


  1. Mutations of presenilin genes in dilated cardiomyopathy and heart failure. Li, D., Parks, S.B., Kushner, J.D., Nauman, D., Burgess, D., Ludwigsen, S., Partain, J., Nixon, R.R., Allen, C.N., Irwin, R.P., Jakobs, P.M., Litt, M., Hershberger, R.E. Am. J. Hum. Genet. (2006) [Pubmed]
  2. Ectopic white matter neurons, a developmental abnormality that may be caused by the PSEN1 S169L mutation in a case of familial AD with myoclonus and seizures. Takao, M., Ghetti, B., Murrell, J.R., Unverzagt, F.W., Giaccone, G., Tagliavini, F., Bugiani, O., Piccardo, P., Hulette, C.M., Crain, B.J., Farlow, M.R., Heyman, A. J. Neuropathol. Exp. Neurol. (2001) [Pubmed]
  3. A novel presenilin-1 mutation (Leu85Pro) in early-onset Alzheimer disease with spastic paraparesis. Ataka, S., Tomiyama, T., Takuma, H., Yamashita, T., Shimada, H., Tsutada, T., Kawabata, K., Mori, H., Miki, T. Arch. Neurol. (2004) [Pubmed]
  4. Contrasting role of presenilin-1 and presenilin-2 in neuronal differentiation in vitro. Hong, C.S., Caromile, L., Nomata, Y., Mori, H., Bredesen, D.E., Koo, E.H. J. Neurosci. (1999) [Pubmed]
  5. Cyclooxygenase-2 and presenilin-1 gene expression induced by interleukin-1beta and amyloid beta 42 peptide is potentiated by hypoxia in primary human neural cells. Bazan, N.G., Lukiw, W.J. J. Biol. Chem. (2002) [Pubmed]
  6. Alzheimer-associated C allele of the promoter polymorphism -22C>T causes a critical neuron-specific decrease of presenilin 1 expression. Theuns, J., Remacle, J., Killick, R., Corsmit, E., Vennekens, K., Huylebroeck, D., Cruts, M., Van Broeckhoven, C. Hum. Mol. Genet. (2003) [Pubmed]
  7. Two novel presenilin 1 gene mutations connected with frontotemporal dementia-like clinical phenotype: genetic and bioinformatic assessment. Zekanowski, C., Golan, M.P., Krzyśko, K.A., Lipczyńska-Łojkowska, W., Filipek, S., Kowalska, A., Rossa, G., Pepłońska, B., Styczyńska, M., Maruszak, A., Religa, D., Wender, M., Kulczycki, J., Barcikowska, M., Kuźnicki, J. Exp. Neurol. (2006) [Pubmed]
  8. Linkage to chromosome 14q in Alzheimer's disease (AD) patients without psychotic symptoms. Avramopoulos, D., Fallin, M.D., Bassett, S.S. Am. J. Med. Genet. B Neuropsychiatr. Genet. (2005) [Pubmed]
  9. Microtubular interactions of presenilin direct kinesis of Abeta peptide and its precursors. Tezapsidis, N., Merz, P.A., Merz, G., Hong, H. FASEB J. (2003) [Pubmed]
  10. Apolipoprotein E and presenilin-1 genotypes in Huntington's disease. Panas, M., Avramopoulos, D., Karadima, G., Petersen, M.B., Vassilopoulos, D. J. Neurol. (1999) [Pubmed]
  11. Association of a presenilin 1 S170F mutation with a novel Alzheimer disease molecular phenotype. Piccini, A., Zanusso, G., Borghi, R., Noviello, C., Monaco, S., Russo, R., Damonte, G., Armirotti, A., Gelati, M., Giordano, R., Zambenedetti, P., Russo, C., Ghetti, B., Tabaton, M. Arch. Neurol. (2007) [Pubmed]
  12. Presenilins Form ER Ca(2+) Leak Channels, a Function Disrupted by Familial Alzheimer's Disease-Linked Mutations. Tu, H., Nelson, O., Bezprozvanny, A., Wang, Z., Lee, S.F., Hao, Y.H., Serneels, L., De Strooper, B., Yu, G., Bezprozvanny, I. Cell (2006) [Pubmed]
  13. Presenilin-Dependent ErbB4 Nuclear Signaling Regulates the Timing of Astrogenesis in the Developing Brain. Sardi, S.P., Murtie, J., Koirala, S., Patten, B.A., Corfas, G. Cell (2006) [Pubmed]
  14. Secrets of a secretase: N-cadherin proteolysis regulates CBP function. Rao, V.R., Finkbeiner, S. Cell (2003) [Pubmed]
  15. A CBP binding transcriptional repressor produced by the PS1/epsilon-cleavage of N-cadherin is inhibited by PS1 FAD mutations. Marambaud, P., Wen, P.H., Dutt, A., Shioi, J., Takashima, A., Siman, R., Robakis, N.K. Cell (2003) [Pubmed]
  16. Akt activity in presenilin 1 wild-type and mutation transfected human SH-SY5Y neuroblastoma cells after serum deprivation and high glucose stress. Vestling, M., Wiehager, B., Tanii, H., Cowburn, R.F. J. Neurosci. Res. (2001) [Pubmed]
  17. Presenilin-1 differentially facilitates endoproteolysis of the beta-amyloid precursor protein and Notch. Capell, A., Steiner, H., Romig, H., Keck, S., Baader, M., Grim, M.G., Baumeister, R., Haass, C. Nat. Cell Biol. (2000) [Pubmed]
  18. E280A PS-1 mutation causes Alzheimer's disease but age of onset is not modified by ApoE alleles. Lendon, C.L., Martinez, A., Behrens, I.M., Kosik, K.S., Madrigal, L., Norton, J., Neuman, R., Myers, A., Busfield, F., Wragg, M., Arcos, M., Arango Viana, J.C., Ossa, J., Ruiz, A., Goate, A.M., Lopera, F. Hum. Mutat. (1997) [Pubmed]
  19. The over-expression of the wild type or mutant forms of the presenilin-1 protein alters glycoprotein processing in a human neuroblastoma cell line. Farquhar, M.J., Gray, C.W., Breen, K.C. Neurosci. Lett. (2003) [Pubmed]
  20. A unique gene expression signature discriminates familial Alzheimer's disease mutation carriers from their wild-type siblings. Nagasaka, Y., Dillner, K., Ebise, H., Teramoto, R., Nakagawa, H., Lilius, L., Axelman, K., Forsell, C., Ito, A., Winblad, B., Kimura, T., Graff, C. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  21. Alzheimer-associated presenilins 1 and 2: neuronal expression in brain and localization to intracellular membranes in mammalian cells. Kovacs, D.M., Fausett, H.J., Page, K.J., Kim, T.W., Moir, R.D., Merriam, D.E., Hollister, R.D., Hallmark, O.G., Mancini, R., Felsenstein, K.M., Hyman, B.T., Tanzi, R.E., Wasco, W. Nat. Med. (1996) [Pubmed]
  22. 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. Scheuner, D., Eckman, C., Jensen, M., Song, X., Citron, M., Suzuki, N., Bird, T.D., Hardy, J., Hutton, M., Kukull, W., Larson, E., Levy-Lahad, E., Viitanen, M., Peskind, E., Poorkaj, P., Schellenberg, G., Tanzi, R., Wasco, W., Lannfelt, L., Selkoe, D., Younkin, S. Nat. Med. (1996) [Pubmed]
  23. Presenilin-1 forms complexes with the cadherin/catenin cell-cell adhesion system and is recruited to intercellular and synaptic contacts. Georgakopoulos, A., Marambaud, P., Efthimiopoulos, S., Shioi, J., Cui, W., Li, H.C., Schütte, M., Gordon, R., Holstein, G.R., Martinelli, G., Mehta, P., Friedrich, V.L., Robakis, N.K. Mol. Cell (1999) [Pubmed]
  24. Presenilin-1 affects trafficking and processing of betaAPP and is targeted in a complex with nicastrin to the plasma membrane. Kaether, C., Lammich, S., Edbauer, D., Ertl, M., Rietdorf, J., Capell, A., Steiner, H., Haass, C. J. Cell Biol. (2002) [Pubmed]
  25. Identification of ubiquilin, a novel presenilin interactor that increases presenilin protein accumulation. Mah, A.L., Perry, G., Smith, M.A., Monteiro, M.J. J. Cell Biol. (2000) [Pubmed]
  26. A novel presenilin 1 mutation (L174 M) in a large Cuban family with early onset Alzheimer disease. Bertoli Avella, A.M., Marcheco Teruel, B., Llibre Rodriguez, J.J., Gomez Viera, N., Borrajero Martinez, I., Severijnen, E.A., Joosse, M., van Duijn, C.M., Heredero Baute, L., Heutink, P. Neurogenetics (2002) [Pubmed]
  27. Presenilin complexes with the C-terminal fragments of amyloid precursor protein at the sites of amyloid beta-protein generation. Xia, W., Ray, W.J., Ostaszewski, B.L., Rahmati, T., Kimberly, W.T., Wolfe, M.S., Zhang, J., Goate, A.M., Selkoe, D.J. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  28. The Glu318Gly mutation of the presenilin-1 gene does not necessarily cause Alzheimer's disease. Mattila, K.M., Forsell, C., Pirttilä, T., Rinne, J.O., Lehtimäki, T., Röyttä, M., Lilius, L., Eerola, A., St George-Hyslop, P.H., Frey, H., Lannfelt, L. Ann. Neurol. (1998) [Pubmed]
  29. Glucose and endoplasmic reticulum calcium channels regulate HIF-1beta via presenilin in pancreatic beta-cells. Dror, V., Kalynyak, T.B., Bychkivska, Y., Frey, M.H., Tee, M., Jeffrey, K.D., Nguyen, V., Luciani, D.S., Johnson, J.D. J. Biol. Chem. (2008) [Pubmed]
  30. Presenilin and nicastrin regulate each other and determine amyloid beta-peptide production via complex formation. Edbauer, D., Winkler, E., Haass, C., Steiner, H. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  31. The role of presenilin-1 in the gamma-secretase cleavage of the amyloid precursor protein of Alzheimer's disease. Octave, J.N., Essalmani, R., Tasiaux, B., Menager, J., Czech, C., Mercken, L. J. Biol. Chem. (2000) [Pubmed]
  32. Syntaxin 5 interacts with presenilin holoproteins, but not with their N- or C-terminal fragments, and affects beta-amyloid peptide production. Suga, K., Tomiyama, T., Mori, H., Akagawa, K. Biochem. J. (2004) [Pubmed]
  33. The presenilin 1 protein is a component of a high molecular weight intracellular complex that contains beta-catenin. Yu, G., Chen, F., Levesque, G., Nishimura, M., Zhang, D.M., Levesque, L., Rogaeva, E., Xu, D., Liang, Y., Duthie, M., St George-Hyslop, P.H., Fraser, P.E. J. Biol. Chem. (1998) [Pubmed]
  34. GSK3beta activity modifies the localization and function of presenilin 1. Uemura, K., Kuzuya, A., Shimozono, Y., Aoyagi, N., Ando, K., Shimohama, S., Kinoshita, A. J. Biol. Chem. (2007) [Pubmed]
  35. Presenilins and Alzheimer's disease: biological functions and pathogenic mechanisms. Czech, C., Tremp, G., Pradier, L. Prog. Neurobiol. (2000) [Pubmed]
  36. Impas 1 possesses endoproteolytic activity against multipass membrane protein substrate cleaving the presenilin 1 holoprotein. Moliaka, Y.K., Grigorenko, A., Madera, D., Rogaev, E.I. FEBS Lett. (2004) [Pubmed]
  37. The Alzheimer's disease-associated presenilins are differentially phosphorylated proteins located predominantly within the endoplasmic reticulum. Walter, J., Capell, A., Grünberg, J., Pesold, B., Schindzielorz, A., Prior, R., Podlisny, M.B., Fraser, P., Hyslop, P.S., Selkoe, D.J., Haass, C. Mol. Med. (1996) [Pubmed]
  38. Impaired proteolytic processing of presenilin-1 in chromosome 14-linked familial Alzheimer's disease patient lymphocytes. Takahashi, H., Mercken, M., Honda, T., Saito, Y., Murayama, M., Song, S., Takashima, A. Neurosci. Lett. (1999) [Pubmed]
  39. Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Lin, X., Koelsch, G., Wu, S., Downs, D., Dashti, A., Tang, J. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  40. The presenilin 1 deltaE9 mutation gives enhanced basal phospholipase C activity and a resultant increase in intracellular calcium concentrations. Cedazo-Minguez, A., Popescu, B.O., Ankarcrona, M., Nishimura, T., Cowburn, R.F. J. Biol. Chem. (2002) [Pubmed]
  41. Presenilin 1 mutations activate gamma 42-secretase but reciprocally inhibit epsilon-secretase cleavage of amyloid precursor protein (APP) and S3-cleavage of notch. Chen, F., Gu, Y., Hasegawa, H., Ruan, X., Arawaka, S., Fraser, P., Westaway, D., Mount, H., St George-Hyslop, P. J. Biol. Chem. (2002) [Pubmed]
  42. Presenilin-1 maintains a nine-transmembrane topology throughout the secretory pathway. Spasic, D., Tolia, A., Dillen, K., Baert, V., De Strooper, B., Vrijens, S., Annaert, W. J. Biol. Chem. (2006) [Pubmed]
  43. Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Abeta 42 production. Moehlmann, T., Winkler, E., Xia, X., Edbauer, D., Murrell, J., Capell, A., Kaether, C., Zheng, H., Ghetti, B., Haass, C., Steiner, H. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  44. Inhibiting amyloid precursor protein C-terminal cleavage promotes an interaction with presenilin 1. Verdile, G., Martins, R.N., Duthie, M., Holmes, E., St George-Hyslop, P.H., Fraser, P.E. J. Biol. Chem. (2000) [Pubmed]
  45. Calsenilin: a calcium-binding protein that interacts with the presenilins and regulates the levels of a presenilin fragment. Buxbaum, J.D., Choi, E.K., Luo, Y., Lilliehook, C., Crowley, A.C., Merriam, D.E., Wasco, W. Nat. Med. (1998) [Pubmed]
  46. Reconstitution of gamma-secretase activity. Edbauer, D., Winkler, E., Regula, J.T., Pesold, B., Steiner, H., Haass, C. Nat. Cell Biol. (2003) [Pubmed]
  47. APH1 polar transmembrane residues regulate the assembly and activity of presenilin complexes. Pardossi-Piquard, R., Yang, S.P., Kanemoto, S., Gu, Y., Chen, F., Böhm, C., Sevalle, J., Li, T., Wong, P.C., Checler, F., Schmitt-Ulms, G., St George-Hyslop, P., Fraser, P.E. J. Biol. Chem. (2009) [Pubmed]
  48. Gamma-secretase activity is not involved in presenilin-mediated regulation of beta-catenin. Meredith, J.E., Wang, Q., Mitchell, T.J., Olson, R.E., Zaczek, R., Stern, A.M., Seiffert, D. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  49. Distribution of presenilin 1 and 2 and their relation to Notch receptors and ligands in human embryonic/foetal central nervous system. Kostyszyn, B., Cowburn, R.F., Seiger, A., Kjaeldgaard, A., Sundström, E. Brain Res. Dev. Brain Res. (2004) [Pubmed]
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