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PSEN2  -  presenilin 2 (Alzheimer disease 4)

Homo sapiens

 
 
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Disease relevance of PSEN2

  • These data indicate that PSEN1 and PSEN2 mutations are associated with DCM and heart failure and implicate novel mechanisms of myocardial disease [1].
  • By using stable transfection of antisense cDNAs, we studied the functions of PS1 and PS2 during neuronal differentiation in the NTera2 human teratocarcinoma (NT2) cell line [2].
  • Moreover, we observed similarly reduced taxol/GTP-stimulated tubulin polymerization from gray matter obtained from patients with AD caused by PSEN2 N141I mutation or frontotemporal dementia with parkinsonism linked to chromosome-17 caused (FTDP-17) by TAU V337M or P301L mutation [3].
  • Mutations in the genes encoding the presenilins (PS1 and PS2) and amyloid precursor protein (APP) are associated with FAD, whereas mutations in the prion protein (PrP) gene are associated with prion disease [4].
  • CONCLUSION: PS2 and cathepsin D are independent prognostic factors in primary breast cancer and lymph node-negative patients [5].
 

Psychiatry related information on PSEN2

 

High impact information on PSEN2

  • Deficient Ca(2+) signaling in DKO MEFs can be rescued by expression of wild-type PS1 or PS2 but not by expression of PS1-M146V or PS2-N141I mutants [10].
  • Using this PS2 domain in the yeast two-hybrid system, we have identified a neuronal protein that binds calcium and presenilin, which we call calsenilin [11].
  • Analysis of PS2 immunoprecipitates revealed that a fraction of APP was associated with the PS2 immunocomplexes [12].
  • Formation of stable complexes between two Alzheimer's disease gene products: presenilin-2 and beta-amyloid precursor protein [12].
  • 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 [13].
 

Chemical compound and disease context of PSEN2

  • PURPOSE: Evaluation of the prognostic value of cytosolic PS2 (pS2 protein) and cathepsin D in a large series of breast cancer patients by multivariate analysis taking into account steroid receptors and conventional prognostic factors [5].
  • In six of the subjects, PS for transport from brain to blood over the brain glucose distribution volume, PS2/Ve decreased under hyperinsulinemia, from a baseline value of 6.56 (3.0-14.9) to 3.86 (1.41-5.32), and restored to a value of 3.8 (2.8-12.1) min-1 after insulin challenge [14].
  • The two polysaccharides differ only in the ring size of shewanellose and have the following structures:Shewanellose has been previously identified in a phenol-soluble polysaccharide from Shewanella putrefaciens A6, which shows a close structural similarity to PS2 [15].
  • The lipopolysaccharide of the bacterium Morganella morganii (strain KF 1676, RK 4222) yielded two polysaccharides, PS1 and PS2, when subjected to mild acid degradation followed by GPC [15].
  • Modulation of proliferation, estradiol receptors and estrogen regulated protein PS2/BCEI in human breast cancer cell lines by gamma interferon [16].
 

Biological context of PSEN2

 

Anatomical context of PSEN2

 

Associations of PSEN2 with chemical compounds

  • RESULTS: We found a missense mutation at codon 430 of the PSEN2 gene that predicts a threonine-to-methionine substitution [22].
  • Yeast two-hybrid (Y2H) interaction, glutathione S-transferase pull-down experiments, and colocalization of the proteins expressed in vivo, together with coimmunoprecipitation and cell fractionation studies, provide compelling evidence that ubiquilin interacts with both PS1 and PS2 [23].
  • Expression of antisense PS1 resulted in a failure of the clones to differentiate into neurons after retinoic acid induction, whereas cells transfected with antisense PS2 differentiated normally [2].
  • Furthermore, endoproteolysis of the exogenous Asp mutant PS2 is absent, and endogenous PS1 C-terminal fragments are diminished to undetectable levels [24].
  • 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 [25].
 

Physical interactions of PSEN2

  • In addition, a second region in the extracellular domain of APP also interacted with PS2 [26].
  • Alzheimer's disease-associated presenilin 2 interacts with DRAL, an LIM-domain protein [27].
  • In gel retardation experiments, antagonist (LY117018) nuclear ER complexes bound to either PS2 or VitA2ERE migrated more slowly than agonist complexes, indicating that the slower migrating form of the complex was not due to the DNA sequence [28].
  • The average unidirectional extraction of L-lactate was 15%; the transport from the blood to the brain (PS1) was 0.081 ml g-1 min-1 and the transport from the brain to the blood (PS2) was on the same order of magnitude [29].
  • By yeast two-hybrid assays, we found that both EF-hands 3 and 4 of calmyrin must be intact for calmyrin to interact with PS2-loop sequences [30].
  • We reveal that the equilibrium of PS1- and PS2-containing active complexes is dynamic and altered by overexpression of Pen2 or PS1 mutants and that formation of PS2 complexes is positively correlated with increased Abeta42:Abeta40 ratios [31].
 

Enzymatic interactions of PSEN2

  • 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 [32].
 

Regulatory relationships of PSEN2

  • High total levels of intracellular Abeta were observed in cells expressing mutant PS2 because of a marked elevation of Abeta42 [20].
  • By contrast, PS2 mRNA expression was upregulated substantially in SK-N-SH cells by exposure to TNF-alpha and in U-373MG cells by treatment with IFN-gamma, whereas it was downregulated in both NTera2-N and U-373 MG cells following exposure to IL-1beta or PMA [33].
  • Calcium binding sequences in calmyrin regulates interaction with presenilin-2 [30].
  • Fifty cases of late onset sporadic Alzheimer disease and 50 age-matched controls indicated no association with an exon 3 polymorphism of the presenilin 2 gene [34].
 

Other interactions of PSEN2

 

Analytical, diagnostic and therapeutic context of PSEN2

  • Yeast two-hybrid liquid assays, affinity chromatography, and coimmunoprecipitation experiments confirm binding between PS2 and calmyrin [36].
  • Direct evidence for apoptosis was obtained by double staining for terminal deoxynucleotide transferase nick end labeling (TUNEL) and PS-2 expression and by following green fluorescent protein-tagged PS-2 over time [18].
  • Furthermore, when APP forms were evaluated in platelet homogenates by means of Western blots analysis with appropriate antibody, no difference was found in the pattern of APP forms in presence of PS2 mutation in platelets, compared with control subjects [39].
  • Employing in situ hybridization, we demonstrate that the expression patterns of PS1 and PS2 in the brain are extremely similar to each other and that messages for both are primarily detectable in neuronal populations [40].
  • The in vitro interaction was confirmed by affinity column assay and the physiological interactions between endogenous PS2 and DRAL by co-immunoprecipitation from human lung fibroblast MRC5 cells [27].

References

  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. 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]
  3. Diminished taxol/GTP-stimulated tubulin polymerization in diseased region of brain from patients with late-onset or inherited Alzheimer's disease or frontotemporal dementia with parkinsonism linked to chromosome-17 but not individuals with mild cognitive impairment. Boutté, A.M., Neely, M.D., Bird, T.D., Montine, K.S., Montine, T.J. J. Alzheimers Dis. (2005) [Pubmed]
  4. High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes. Finckh, U., Müller-Thomsen, T., Mann, U., Eggers, C., Marksteiner, J., Meins, W., Binetti, G., Alberici, A., Hock, C., Nitsch, R.M., Gal, A. Am. J. Hum. Genet. (2000) [Pubmed]
  5. Prognostic value of PS2 and cathepsin D in 710 human primary breast tumors: multivariate analysis. Foekens, J.A., van Putten, W.L., Portengen, H., de Koning, H.Y., Thirion, B., Alexieva-Figusch, J., Klijn, J.G. J. Clin. Oncol. (1993) [Pubmed]
  6. Mean age-of-onset of familial alzheimer disease caused by presenilin mutations correlates with both increased Abeta42 and decreased Abeta40. Kumar-Singh, S., Theuns, J., Van Broeck, B., Pirici, D., Vennekens, K., Corsmit, E., Cruts, M., Dermaut, B., Wang, R., Van Broeckhoven, C. Hum. Mutat. (2006) [Pubmed]
  7. Reduction of Ca2+ stores and capacitative Ca2+ entry is associated with the familial Alzheimer's disease presenilin-2 T122R mutation and anticipates the onset of dementia. Giacomello, M., Barbiero, L., Zatti, G., Squitti, R., Binetti, G., Pozzan, T., Fasolato, C., Ghidoni, R., Pizzo, P. Neurobiol. Dis. (2005) [Pubmed]
  8. Are premorbid personality traits linked to the risk of Alzheimer's Disease? A case series of subjects with familial mutation. Balestrieri, M., Nacmias, B., Sorbi, S., Marcon, G. Psychotherapy and psychosomatics. (2000) [Pubmed]
  9. Expression of truncated presenilin 2 splice variant in Alzheimer's disease, bipolar disorder, and schizophrenia brain cortex. Smith, M.J., Sharples, R.A., Evin, G., McLean, C.A., Dean, B., Pavey, G., Fantino, E., Cotton, R.G., Imaizumi, K., Masters, C.L., Cappai, R., Culvenor, J.G. Brain Res. Mol. Brain Res. (2004) [Pubmed]
  10. 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]
  11. 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]
  12. Formation of stable complexes between two Alzheimer's disease gene products: presenilin-2 and beta-amyloid precursor protein. Weidemann, A., Paliga, K., Dürrwang, U., Czech, C., Evin, G., Masters, C.L., Beyreuther, K. Nat. Med. (1997) [Pubmed]
  13. 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]
  14. High dose insulin does not increase glucose transfer across the blood-brain barrier in humans: a re-evaluation. Knudsen, G.M., Hasselbalch, S.G., Hertz, M.M., Paulson, O.B. Eur. J. Clin. Invest. (1999) [Pubmed]
  15. Structural investigation of the O-specific polysaccharides of Morganella morganii consisting of two higher sugars. Kilcoyne, M., Shashkov, A.S., Senchenkova, S.A., Knirel, Y.A., Vinogradov, E.V., Radziejewska-Lebrecht, J., Galimska-Stypa, R., Savage, A.V. Carbohydr. Res. (2002) [Pubmed]
  16. Modulation of proliferation, estradiol receptors and estrogen regulated protein PS2/BCEI in human breast cancer cell lines by gamma interferon. Solary, E., Prud'homme, J.F., Gauville, C., Magdelenat, H., Calvo, F. J. Biol. Regul. Homeost. Agents (1991) [Pubmed]
  17. Regulatory region variability in the human presenilin-2 (PSEN2) gene: potential contribution to the gene activity and risk for AD. Riazanskaia, N., Lukiw, W.J., Grigorenko, A., Korovaitseva, G., Dvoryanchikov, G., Moliaka, Y., Nicolaou, M., Farrer, L., Bazan, N.G., Rogaev, E. Mol. Psychiatry (2002) [Pubmed]
  18. Increased apoptosis arising from increased expression of the Alzheimer's disease-associated presenilin-2 mutation (N141I). Janicki, S., Monteiro, M.J. J. Cell Biol. (1997) [Pubmed]
  19. Presenilin 2 interacts with sorcin, a modulator of the ryanodine receptor. Pack-Chung, E., Meyers, M.B., Pettingell, W.P., Moir, R.D., Brownawell, A.M., Cheng, I., Tanzi, R.E., Kim, T.W. J. Biol. Chem. (2000) [Pubmed]
  20. Enhanced generation of intracellular Abeta42 amyloid peptide by mutation of presenilins PS1 and PS2. Takeda, K., Araki, W., Tabira, T. Eur. J. Neurosci. (2004) [Pubmed]
  21. Widespread immunoreactivity of presenilin in neurons of normal and Alzheimer's disease brains: double-labeling immunohistochemical study. Uchihara, T., el Hachimi, H.K., Duyckaerts, C., Foncin, J.F., Fraser, P.E., Levesque, L., St George-Hyslop, P.H., Hauw, J.J. Acta Neuropathol. (1996) [Pubmed]
  22. A novel mutation in the PSEN2 gene (T430M) associated with variable expression in a family with early-onset Alzheimer disease. Ezquerra, M., Lleó, A., Castellví, M., Queralt, R., Santacruz, P., Pastor, P., Molinuevo, J.L., Blesa, R., Oliva, R. Arch. Neurol. (2003) [Pubmed]
  23. 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]
  24. The transmembrane aspartates in presenilin 1 and 2 are obligatory for gamma-secretase activity and amyloid beta-protein generation. Kimberly, W.T., Xia, W., Rahmati, T., Wolfe, M.S., Selkoe, D.J. J. Biol. Chem. (2000) [Pubmed]
  25. 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]
  26. Mapping the APP/presenilin (PS) binding domains: the hydrophilic N-terminus of PS2 is sufficient for interaction with APP and can displace APP/PS1 interaction. Pradier, L., Carpentier, N., Delalonde, L., Clavel, N., Bock, M.D., Buée, L., Mercken, L., Tocqué, B., Czech, C. Neurobiol. Dis. (1999) [Pubmed]
  27. Alzheimer's disease-associated presenilin 2 interacts with DRAL, an LIM-domain protein. Tanahashi, H., Tabira, T. Hum. Mol. Genet. (2000) [Pubmed]
  28. Uterine estrogen receptor-DNA complexes: effects of different ERE sequences, ligands, and receptor forms. Curtis, S.W., Korach, K.S. Mol. Endocrinol. (1991) [Pubmed]
  29. Kinetic analysis of the human blood-brain barrier transport of lactate and its influence by hypercapnia. Knudsen, G.M., Paulson, O.B., Hertz, M.M. J. Cereb. Blood Flow Metab. (1991) [Pubmed]
  30. Calcium binding sequences in calmyrin regulates interaction with presenilin-2. Zhu, J., Stabler, S.M., Ames, J.B., Baskakov, I., Monteiro, M.J. Exp. Cell Res. (2004) [Pubmed]
  31. Pen2 and presenilin-1 modulate the dynamic equilibrium of presenilin-1 and presenilin-2 gamma-secretase complexes. Placanica, L., Tarassishin, L., Yang, G., Peethumnongsin, E., Kim, S.H., Zheng, H., Sisodia, S.S., Li, Y.M. J. Biol. Chem. (2009) [Pubmed]
  32. 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]
  33. Constitutive and cytokine-regulated expression of presenilin-1 and presenilin-2 genes in human neural cell lines. Satoh, J., Kuroda, Y. Neuropathol. Appl. Neurobiol. (1999) [Pubmed]
  34. Presenilin-2 mutation and polymorphism in Japanese Alzheimer disease patients. Tanimukai, H., Tsujio, I., Hashimoto, R., Kudo, T., Kamino, K., Shinozaki, K., Takeda, M. Clin. Chim. Acta (1999) [Pubmed]
  35. Endoplasmic reticulum stress-inducible protein, Herp, enhances presenilin-mediated generation of amyloid beta-protein. Sai, X., Kawamura, Y., Kokame, K., Yamaguchi, H., Shiraishi, H., Suzuki, R., Suzuki, T., Kawaichi, M., Miyata, T., Kitamura, T., De Strooper, B., Yanagisawa, K., Komano, H. J. Biol. Chem. (2002) [Pubmed]
  36. A myristoylated calcium-binding protein that preferentially interacts with the Alzheimer's disease presenilin 2 protein. Stabler, S.M., Ostrowski, L.L., Janicki, S.M., Monteiro, M.J. J. Cell Biol. (1999) [Pubmed]
  37. Monogenic determinants of familial Alzheimer's disease: presenilin-2 mutations. Renbaum, P., Levy-Lahad, E. Cell. Mol. Life Sci. (1998) [Pubmed]
  38. Evaluation of multiple presenilin 2 SNPs for association with early-onset sporadic Alzheimer disease. Howell, W.M., Brookes, A.J. Am. J. Med. Genet. (2002) [Pubmed]
  39. Presenilin 2 mutation does not influence expression and concentration of APP forms in human platelets. Pastorino, L., Colciaghi, F., Marcon, G., Borroni, B., Cottini, E., Cattabeni, F., Padovani, A., Di Luca, M. Mol. Med. (2000) [Pubmed]
  40. 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]
 
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