Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/10/17 14:12:00」(JST)

wiki en

Presenilin-1 (PS-1) is a protein that in humans is encoded by the PSEN1 gene.^[1] Presenilin 1 is one of the four core proteins in presenilin complex, which mediate the regulated proteolytic events of several proteins in the cell, including gamma secretase.^[2] Gamma-secretase is considered to play a very important role in generation of beta amyloid, accumulation of which is related to the onset of Alzheimer’s Disease, from the beta-amyloid precursor protein.^[3]

Structure[edit]

Presenilin possesses a 9 transmembrane topology, with an extracellular C-terminus and a cytosolic N-terminus.^[4]^[5] Presenilin is subject to undergo endo-proteolytic processing to produce ~27-28 kDa N-terminal and ~16-17 kDa C-terminal fragments in humans.^[6] Furthermore, presenilin exists in the cell mainly as a heterodimer of the C-terminal and N-terminus fragments.^[6] When presenilin 1 is over expressed, the full length protein accumulates in an inactive form.^[7] Based on evidence that a gamma-secretase inhibitor binds to the fragments,^[8] the cleaved presenilin complex is considered to be the active form.^[9]

Function[edit]

Alzheimer's disease (AD) patients with an inherited form of the disease carry mutations in the presenilin proteins (PSEN1; PSEN2) or the amyloid precursor protein (APP). These disease-linked mutations result in increased production of the longer form of amyloid beta (main component of amyloid deposits found in AD brains). Presenilins are postulated to regulate APP processing through their effects on gamma secretase, an enzyme that cleaves APP. Also, it is thought that the presenilins are involved in the cleavage of the Notch receptor, such that they either directly regulate gamma secretase activity or themselves are protease enzymes. Multiple alternatively spliced transcript variants have been identified for this gene, the full-length natures of only some have been determined.^[10]

Role in beta-amyloid production[edit]

Transgenic mice that over-expressed mutant presenilin-1 show an increase of beta-amyloid-42(43) in the brain, which suggest presenilin-1 plays an important role in beta-amyloid regulation and can be highly related to Alzheimer’s disease.^[11] Further study conducted in neuronal cultures derived from presenilin-1 deficient mouse embryos. They showed that cleavage by alpha- and beta- secretase was still normal without the presence of presenilin-1. Meanwhile, the cleavage by gamma-cleavage of the transmembrane domain of APP was abolished. A 5-fold drop of amyloid peptide was observed, suggesting that deficiency of presenilin-1 can down regulate amyloid and inhibition of presenilin-1 can be a potential method for anti-amyloidogenic therapy in Alzheimer’s disease.^[12] Extensive study on the role of presenilin-1 in amyloid production has been conducted to improve our understanding of Alzheimer’s disease.^[13]^[14]

Role in Notch signaling pathway[edit]

In Notch signaling, critical proteolytic reactions takes place during maturation and activation of Notch membrane receptor.^[15] Notch1 is cleaved extracellularlly at site1 (S1) and two polypeptides are produce to form a heterodimer receptor on the cell surface.^[16] After the formation of receptor, Notch1 is further cleaved in site 3(S3)^[17] and release Notch1 intracellular domain (NICD) form the membrane.^[18]

Presenilin 1 has been shown to play an important role in proteolytic process. In the prenilin 1 null mutant drosophila, Notch signaling is abolished and it displays a notch-like lethal phenotype.^[19] Moreover, in mammalian cells, deficiency of PSEN1 also causes the defect in the proteolytic release of NICD from a truncated Notch construct. The same step can be also blocked by several gamma-secretase inhibitors, shown in the same study.^[20] These evidences collectively suggest a critical role of presenilin 1 in the Notch signaling pathway.

Role in Wnt signaling pathway[edit]

Wnt signaling pathway has been shown to be involved in several critical steps in embryogenensis and development. Presenilin 1 has been shown to form a complex with beta-catenin, an important component in Wnt signaling, and stabilized beta-catenin.^[21] Mutant of presenilin-1 that reduces the ability to stable beta-catenin complex will lead to hyperactive degradation of beta-catenin in the brains of transgenic mice.^[21]

Considered as a negative regulator in wnt signaling pathway, presenilin-1 was also found to be played a role in beta-catenin phosphorylation.^[22] Beta-catenin is coupled by presenilin-1 and under a sequential phosphorylation by two kinase activities.^[22] The study also further illustrates the deficiency of presenilin 1 will disconnect the sequential phosphorylation and thus disrupt the normal wnt signaling pathway.^[22]

Role in cancer[edit]

In addition to its role in Alzheimer’s disease, presenilin-1 also found to be important in cancer. A study of broad range gene expression was conducted on human malignant melanoma. Researchers classified the malignant melanoma cell lines into two types. The study showed that presenilin-1 is down regulated in cell type while it is overexpressed in the other cell type.^[23] Another study on multidrug resistance (MDR) cell line also reveals a role of presenilin-1 in cancer development. Because of the development to the resistance to chemical, MDR cells become a critical factor on the success of cancer chemotherapy.^[24] In the study, researcher tried to explore the molecular mechanism by looking into the expression of Notch1 intracellular (N1IC) domain and presenilin 1. They found that there is higher level expression of both protein and a multidrug resistance-associated protein 1 (ABCC1) was also found to be regulated by N1IC, which suggest a mechanism of ABCC1 regulated by presenilin 1 and notch signaling.^[25]

Interactions[edit]

PSEN1 has been shown to interact with:

BCL2,^[26]
CTNNB1,^[27]^[28]^[29]
CTNND1,^[30]
FLNB,^[31]
GFAP,^[32]
ICAM5,^[33]
KCNIP3,^[34]^[35]
NCSTN,^[36]^[37]^[38]^[39]^[40]
PKP4,^[41] and
UBQLN1.^[42]

References[edit]

^ Schellenberg GD, Bird TD, Wijsman EM, Orr HT, Anderson L, Nemens E, White JA, Bonnycastle L, Weber JL, Alonso ME, et al. (Nov 1992). "Genetic linkage evidence for a familial Alzheimer's disease locus on chromosome 14". Science 258 (5082): 668–71. Bibcode:1992Sci...258..668S. doi:10.1126/science.1411576. PMID 1411576.
^ St George-Hyslop P, Fraser PE (January 2012). "Assembly of the presenilin γ-/ε-secretase complex". J. Neurochem. 120 Suppl 1: 84–8. doi:10.1111/j.1471-4159.2011.07505.x. PMID 22122073.
^ Selkoe DJ (1994). "Cell biology of the amyloid beta-protein precursor and the mechanism of Alzheimer's disease". Annu. Rev. Cell Biol. 10: 373–403. doi:10.1146/annurev.cb.10.110194.002105. PMID 7888181.
^ Laudon H, Hansson EM, Melén K, Bergman A, Farmery MR, Winblad B, Lendahl U, von Heijne G, Näslund J (October 2005). "A nine-transmembrane domain topology for presenilin 1". J. Biol. Chem. 280 (42): 35352–60. doi:10.1074/jbc.M507217200. PMID 16046406.
^ Spasic D, Annaert W (February 2008). "Building gamma-secretase: the bits and pieces". J. Cell. Sci. 121 (Pt 4): 413–20. doi:10.1242/jcs.015255. PMID 18256384.
^ ^a ^b Thinakaran G, Borchelt DR, Lee MK, Slunt HH, Spitzer L, Kim G, Ratovitsky T, Davenport F, Nordstedt C, Seeger M, Hardy J, Levey AI, Gandy SE, Jenkins NA, Copeland NG, Price DL, Sisodia SS (July 1996). "Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo". Neuron 17 (1): 181–90. doi:10.1016/S0896-6273(00)80291-3. PMID 8755489.
^ Ratovitski T, Slunt HH, Thinakaran G, Price DL, Sisodia SS, Borchelt DR (September 1997). "Endoproteolytic processing and stabilization of wild-type and mutant presenilin". J. Biol. Chem. 272 (39): 24536–41. doi:10.1074/jbc.272.39.24536. PMID 9305918.
^ Li YM, Xu M, Lai MT, Huang Q, Castro JL, DiMuzio-Mower J, Harrison T, Lellis C, Nadin A, Neduvelil JG, Register RB, Sardana MK, Shearman MS, Smith AL, Shi XP, Yin KC, Shafer JA, Gardell SJ (June 2000). "Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1". Nature 405 (6787): 689–94. doi:10.1038/35015085. PMID 10864326.
^ Brunkan AL, Martinez M, Walker ES, Goate AM (May 2005). "Presenilin endoproteolysis is an intramolecular cleavage". Mol. Cell. Neurosci. 29 (1): 65–73. doi:10.1016/j.mcn.2004.12.012. PMID 15866047.
^ "Entrez Gene: PSEN1 presenilin 1 (Alzheimer disease 3)".
^ Duff K, Eckman C, Zehr C, Yu X, Prada CM, Perez-tur J, Hutton M, Buee L, Harigaya Y, Yager D, Morgan D, Gordon MN, Holcomb L, Refolo L, Zenk B, Hardy J, Younkin S (October 1996). "Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1". Nature 383 (6602): 710–3. Bibcode:1996Natur.383..710D. doi:10.1038/383710a0. PMID 8878479.
^ De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, Von Figura K, Van Leuven F (January 1998). "Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein". Nature 391 (6665): 387–90. Bibcode:1998Natur.391..387D. doi:10.1038/34910. PMID 9450754.
^ Pitsi D, Octave JN (June 2004). "Presenilin 1 stabilizes the C-terminal fragment of the amyloid precursor protein independently of gamma-secretase activity". J. Biol. Chem. 279 (24): 25333–8. doi:10.1074/jbc.M312710200. PMID 15087467.
^ Phiel CJ, Wilson CA, Lee VM, Klein PS (May 2003). "GSK-3alpha regulates production of Alzheimer's disease amyloid-beta peptides". Nature 423 (6938): 435–9. Bibcode:2003Natur.423..435P. doi:10.1038/nature01640. PMID 12761548.
^ Chan YM, Jan YN (August 1998). "Roles for proteolysis and trafficking in notch maturation and signal transduction". Cell 94 (4): 423–6. doi:10.1016/S0092-8674(00)81583-4. PMID 9727485.
^ Logeat F, Bessia C, Brou C, LeBail O, Jarriault S, Seidah NG, Israël A (July 1998). "The Notch1 receptor is cleaved constitutively by a furin-like convertase". Proc. Natl. Acad. Sci. U.S.A. 95 (14): 8108–12. Bibcode:1998PNAS...95.8108L. doi:10.1073/pnas.95.14.8108. PMC 20937. PMID 9653148.
^ Schroeter EH, Kisslinger JA, Kopan R (May 1998). "Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain". Nature 393 (6683): 382–6. Bibcode:1998Natur.393..382S. doi:10.1038/30756. PMID 9620803.
^ Jarriault S, Brou C, Logeat F, Schroeter EH, Kopan R, Israel A (September 1995). "Signalling downstream of activated mammalian Notch". Nature 377 (6547): 355–8. Bibcode:1995Natur.377..355J. doi:10.1038/377355a0. PMID 7566092.
^ Struhl G, Greenwald I (April 1999). "Presenilin is required for activity and nuclear access of Notch in Drosophila". Nature 398 (6727): 522–5. Bibcode:1999Natur.398..522S. doi:10.1038/19091. PMID 10206646.
^ De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, Schroeter EH, Schrijvers V, Wolfe MS, Ray WJ, Goate A, Kopan R (April 1999). "A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain". Nature 398 (6727): 518–22. Bibcode:1999Natur.398..518D. doi:10.1038/19083. PMID 10206645.
^ ^a ^b Zhang C, Wu B, Beglopoulos V, Wines-Samuelson M, Zhang D, Dragatsis I, Südhof TC, Shen J (July 2009). "Presenilins are essential for regulating neurotransmitter release". Nature 460 (7255): 632–6. Bibcode:2009Natur.460..632Z. doi:10.1038/nature08177. PMC 2744588. PMID 19641596.
^ ^a ^b ^c Kang DE, Soriano S, Xia X, Eberhart CG, De Strooper B, Zheng H, Koo EH (September 2002). "Presenilin couples the paired phosphorylation of beta-catenin independent of axin: implications for beta-catenin activation in tumorigenesis". Cell 110 (6): 751–62. doi:10.1016/S0092-8674(02)00970-4. PMID 12297048.
^ Su DM, Zhang Q, Wang X, He P, Zhu YJ, Zhao J, Rennert OM, Su YA (May 2009). "Two types of human malignant melanoma cell lines revealed by expression patterns of mitochondrial and survival-apoptosis genes: implications for malignant melanoma therapy". Mol. Cancer Ther. 8 (5): 1292–304. doi:10.1158/1535-7163.MCT-08-1030. PMC 3128982. PMID 19383853.
^ Gottesman MM, Fojo T, Bates SE (January 2002). "Multidrug resistance in cancer: role of ATP-dependent transporters". Nat. Rev. Cancer 2 (1): 48–58. doi:10.1038/nrc706. PMID 11902585.
^ Cho S, Lu M, He X, Ee PL, Bhat U, Schneider E, Miele L, Beck WT (December 2011). "Notch1 regulates the expression of the multidrug resistance gene ABCC1/MRP1 in cultured cancer cells". Proc. Natl. Acad. Sci. U.S.A. 108 (51): 20778–83. Bibcode:2011PNAS..10820778C. doi:10.1073/pnas.1019452108. PMID 22143792.
^ Alberici A, Moratto D, Benussi L, Gasparini L, Ghidoni R, Gatta LB, Finazzi D, Frisoni GB, Trabucchi M, Growdon JH, Nitsch RM, Binetti G (October 1999). "Presenilin 1 protein directly interacts with Bcl-2". J. Biol. Chem. 274 (43): 30764–9. doi:10.1074/jbc.274.43.30764. PMID 10521466.
^ Tesco G, Kim TW, Diehlmann A, Beyreuther K, Tanzi RE (December 1998). "Abrogation of the presenilin 1/beta-catenin interaction and preservation of the heterodimeric presenilin 1 complex following caspase activation". J. Biol. Chem. 273 (51): 33909–14. doi:10.1074/jbc.273.51.33909. PMID 9852041.
^ Kang DE, Soriano S, Frosch MP, Collins T, Naruse S, Sisodia SS, Leibowitz G, Levine F, Koo EH (June 1999). "Presenilin 1 facilitates the constitutive turnover of beta-catenin: differential activity of Alzheimer's disease-linked PS1 mutants in the beta-catenin-signaling pathway". J. Neurosci. 19 (11): 4229–37. PMID 10341227.
^ Murayama M, Tanaka S, Palacino J, Murayama O, Honda T, Sun X, Yasutake K, Nihonmatsu N, Wolozin B, Takashima A (August 1998). "Direct association of presenilin-1 with beta-catenin". FEBS Lett. 433 (1–2): 73–7. doi:10.1016/S0014-5793(98)00886-2. PMID 9738936.
^ Tanahashi H, Tabira T (February 1999). "Isolation of human delta-catenin and its binding specificity with presenilin 1". NeuroReport 10 (3): 563–8. doi:10.1097/00001756-199902250-00022. PMID 10208590.
^ Zhang W, Han SW, McKeel DW, Goate A, Wu JY (February 1998). "Interaction of presenilins with the filamin family of actin-binding proteins". J. Neurosci. 18 (3): 914–22. PMC 2042137. PMID 9437013.
^ Nielsen AL, Holm IE, Johansen M, Bonven B, Jørgensen P, Jørgensen AL (August 2002). "A new splice variant of glial fibrillary acidic protein, GFAP epsilon, interacts with the presenilin proteins". J. Biol. Chem. 277 (33): 29983–91. doi:10.1074/jbc.M112121200. PMID 12058025.
^ Annaert WG, Esselens C, Baert V, Boeve C, Snellings G, Cupers P, Craessaerts K, De Strooper B (November 2001). "Interaction with telencephalin and the amyloid precursor protein predicts a ring structure for presenilins". Neuron 32 (4): 579–89. doi:10.1016/S0896-6273(01)00512-8. PMID 11719200.
^ Buxbaum JD, Choi EK, Luo Y, Lilliehook C, Crowley AC, Merriam DE, Wasco W (October 1998). "Calsenilin: a calcium-binding protein that interacts with the presenilins and regulates the levels of a presenilin fragment". Nat. Med. 4 (10): 1177–81. doi:10.1038/2673. PMID 9771752.
^ Kashiwa A, Yoshida H, Lee S, Paladino T, Liu Y, Chen Q, Dargusch R, Schubert D, Kimura H (July 2000). "Isolation and characterization of novel presenilin binding protein". J. Neurochem. 75 (1): 109–16. doi:10.1046/j.1471-4159.2000.0750109.x. PMID 10854253.
^ Haffner C, Frauli M, Topp S, Irmler M, Hofmann K, Regula JT, Bally-Cuif L, Haass C (August 2004). "Nicalin and its binding partner Nomo are novel Nodal signaling antagonists". EMBO J. 23 (15): 3041–50. doi:10.1038/sj.emboj.7600307. PMC 514924. PMID 15257293.
^ Baulac S, LaVoie MJ, Kimberly WT, Strahle J, Wolfe MS, Selkoe DJ, Xia W (November 2003). "Functional gamma-secretase complex assembly in Golgi/trans-Golgi network: interactions among presenilin, nicastrin, Aph1, Pen-2, and gamma-secretase substrates". Neurobiol. Dis. 14 (2): 194–204. doi:10.1016/S0969-9961(03)00123-2. PMID 14572442.
^ Gu Y, Chen F, Sanjo N, Kawarai T, Hasegawa H, Duthie M, Li W, Ruan X, Luthra A, Mount HT, Tandon A, Fraser PE, St George-Hyslop P (February 2003). "APH-1 interacts with mature and immature forms of presenilins and nicastrin and may play a role in maturation of presenilin.nicastrin complexes". J. Biol. Chem. 278 (9): 7374–80. doi:10.1074/jbc.M209499200. PMID 12471034.
^ Lee SF, Shah S, Li H, Yu C, Han W, Yu G (November 2002). "Mammalian APH-1 interacts with presenilin and nicastrin and is required for intramembrane proteolysis of amyloid-beta precursor protein and Notch". J. Biol. Chem. 277 (47): 45013–9. doi:10.1074/jbc.M208164200. PMID 12297508.
^ Yu G, Nishimura M, Arawaka S, Levitan D, Zhang L, Tandon A, Song YQ, Rogaeva E, Chen F, Kawarai T, Supala A, Levesque L, Yu H, Yang DS, Holmes E, Milman P, Liang Y, Zhang DM, Xu DH, Sato C, Rogaev E, Smith M, Janus C, Zhang Y, Aebersold R, Farrer LS, Sorbi S, Bruni A, Fraser P, St George-Hyslop P (September 2000). "Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing". Nature 407 (6800): 48–54. doi:10.1038/35024009. PMID 10993067.
^ Stahl B, Diehlmann A, Südhof TC (April 1999). "Direct interaction of Alzheimer's disease-related presenilin 1 with armadillo protein p0071". J. Biol. Chem. 274 (14): 9141–8. doi:10.1074/jbc.274.14.9141. PMID 10092585.
^ Mah AL, Perry G, Smith MA, Monteiro MJ (November 2000). "Identification of ubiquilin, a novel presenilin interactor that increases presenilin protein accumulation". J. Cell Biol. 151 (4): 847–62. doi:10.1083/jcb.151.4.847. PMC 2169435. PMID 11076969.

External links[edit]

GeneReviews/NCBI/NIH/UW entry on Early-Onset Familial Alzheimer Disease

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. アルツハイマー病の遺伝学 genetics of alzheimer disease
2. 成人における早期発症の認知症 early onset dementia in adults
3. Hidradenitis suppurativa (acne inversa): Pathogenesis, clinical features, and diagnosis
4. 認知機能低下および認知症の危険因子 risk factors for cognitive decline and dementia
5. アミロイド疾患の遺伝的要因 genetic factors in the amyloid diseases

English Journal

G206D Mutation of Presenilin-1 Reduces Pen2 Interaction, Increases Aβ42/Aβ40 Ratio and Elevates ER Ca2+ Accumulation.

Chen WT1, Hsieh YF, Huang YJ, Lin CC, Lin YT, Liu YC, Lien CC, Cheng IH.
Molecular neurobiology.Mol Neurobiol.2014 Nov 15. [Epub ahead of print]
Early-onset familial Alzheimer's disease (AD) is most commonly associated with the mutations in presenilin-1 (PS1). PS1 is the catalytic component of the γ-secretase complex, which cleaves amyloid precursor protein to produce amyloid-β (Aβ), the major cause of AD. Presenilin enhancer 2 (Pen2) is
PMID 25394380

A three-dimensional human neural cell culture model of Alzheimer's disease.

Choi SH1, Kim YH2, Hebisch M3, Sliwinski C4, Lee S5, D'Avanzo C4, Chen H4, Hooli B4, Asselin C4, Muffat J6, Klee JB4, Zhang C4, Wainger BJ5, Peitz M7, Kovacs DM4, Woolf CJ5, Wagner SL8, Tanzi RE4, Kim DY4.
Nature.Nature.2014 Nov 13;515(7526):274-8. doi: 10.1038/nature13800. Epub 2014 Oct 12.
Alzheimer's disease is the most common form of dementia, characterized by two pathological hallmarks: amyloid-β plaques and neurofibrillary tangles. The amyloid hypothesis of Alzheimer's disease posits that the excessive accumulation of amyloid-β peptide leads to neurofibrillary tangles composed o
PMID 25307057

Enhancement of β-amyloid oligomer accumulation after intracerebroventricular injection of streptozotocin, which involves central insulin signaling in a transgenic mouse model.

Lin F1, Jia J, Qin W.
Neuroreport.Neuroreport.2014 Nov 12;25(16):1289-95. doi: 10.1097/WNR.0000000000000261.
The β-amyloid (Aβ) oligomer rather than fibrillar Aβ has become the important focus of recent studies on the pathogenesis of Alzheimer's disease (AD). Insulin signaling plays important roles in cognitive disease, such as AD. However, in-vivo evidence for the link between central insulin signaling
PMID 25202927

Japanese Journal

APPswe/PS1dE9マウスにおける記憶障害及び行動異常に関する基礎研究

谷内信彦,新留徹広,杉本八郎
薬学雑誌. 乙号 135(2), 323-329, 2015
… To assess the influence of Aβ pathology on cognitive and non-cognitive behaviors, we examined locomotor activity, motor coordination, and spatial memory in male and female APPswePS1dE9 mice (Alzheimer's disease model, double transgenic mice expressing an amyloid precursor protein with Swedish mutation and a presenilin-1 with deletion of exon 9) at 5 months of age, when the mice had subtle Aβ deposits, and again at 9 months of age, when the mice had numerous Aβ deposits. …
NAID 130004756480

Protective Effects of Ferulic Acid in Amyloid Precursor Protein Plus Presenilin-1 Transgenic Mouse Model of Alzheimer Disease

Yan Ji-Jing,Jung Jun-Sub,Kim Taek-Keun [他]
Biological & pharmaceutical bulletin 36(1), 140-143, 2013-01
NAID 40019536220

Protective Effects of Ferulic Acid in Amyloid Precursor Protein Plus Presenilin-1 Transgenic Mouse Model of Alzheimer Disease

Yan Ji-Jing,Jung Jun-Sub,Kim Taek-Keun,Hasan Md. Ashraful,Hong Chang-Won,Nam Ju-Suk,Song Dong-Keun
Biological and Pharmaceutical Bulletin 36(1), 140-143, 2013
… In the present study, we investigated the effects of ferulic acid in transgenic amyloid precursor protein (APP)swe/presenilin 1 (PS1)dE9 (APP/PS1) mouse model of Alzheimer disease (AD). …
NAID 130001872058

Related Pictures

★リンクテーブル★

リンク元	「プレセニリン1」「プレセニリン-1」

「プレセニリン1」

Presenilin 1
Available structures
PDB	Ortholog search: PDBe, RCSB
List of PDB id codes
	2KR6
Identifiers
Symbols	PSEN1; AD3; FAD; PS-1; PS1; S182
External IDs	OMIM: 104311 MGI: 1202717 HomoloGene: 7186 ChEMBL: 2473 GeneCards: PSEN1 Gene
EC number	3.4.23.-
Gene Ontology
Molecular function	• endopeptidase activity; • aspartic-type endopeptidase activity; • calcium channel activity; • protein binding; • beta-catenin binding; • PDZ domain binding; • cadherin binding;
Cellular component	• Golgi membrane; • kinetochore; • nuclear outer membrane; • mitochondrion; • mitochondrial inner membrane; • lysosomal membrane; • endoplasmic reticulum; • endoplasmic reticulum membrane; • smooth endoplasmic reticulum; • rough endoplasmic reticulum; • Golgi apparatus; • centrosome; • integral to plasma membrane; • cell cortex; • cell surface; • membrane; • integral to membrane; • apical plasma membrane; • Z disc; • axon; • growth cone; • cytoplasmic vesicle; • neuromuscular junction; • nuclear membrane; • ciliary rootlet; • neuronal cell body; • dendritic shaft; • membrane raft; • perinuclear region of cytoplasm; • gamma-secretase complex;
Biological process	• autophagic vacuole assembly; • negative regulation of transcription from RNA polymerase II promoter; • activation of MAPKK activity; • blood vessel development; • cell fate specification; • somitogenesis; • neuron migration; • positive regulation of receptor recycling; • heart looping; • hematopoietic progenitor cell differentiation; • T cell activation involved in immune response; • myeloid leukocyte differentiation; • protein glycosylation; • membrane protein ectodomain proteolysis; • calcium ion transport; • mitochondrial transport; • response to DNA damage stimulus; • response to oxidative stress; • negative regulation of epidermal growth factor-activated receptor activity; • Notch signaling pathway; • Notch receptor processing; • memory; • post-embryonic development; • protein transport; • L-glutamate transport; • choline transport; • synaptic vesicle targeting; • cell-cell adhesion; • protein processing; • cerebral cortex cell migration; • Cajal-Retzius cell differentiation; • dorsal/ventral neural tube patterning; • embryonic limb morphogenesis; • positive regulation of proteasomal ubiquitin-dependent protein catabolic process; • endoplasmic reticulum calcium ion homeostasis; • intracellular signal transduction; • regulation of phosphorylation; • anagen; • amyloid precursor protein catabolic process; • positive regulation of apoptotic process; • negative regulation of apoptotic process; • positive regulation of catalytic activity; • regulation of protein binding; • positive regulation of MAP kinase activity; • negative regulation of neuron apoptotic process; • skin morphogenesis; • regulation of synaptic plasticity; • thymus development; • neuron development; • skeletal system morphogenesis; • brain morphogenesis; • beta-amyloid metabolic process; • epithelial cell proliferation; • negative regulation of axonogenesis; • positive regulation of coagulation; • T cell receptor signaling pathway; • neuron apoptotic process; • negative regulation of ubiquitin-protein ligase activity; • smooth endoplasmic reticulum calcium ion homeostasis; • regulation of synaptic transmission, glutamatergic; • regulation of resting membrane potential; • calcium ion transmembrane transport; • negative regulation of protein ubiquitination involved in ubiquitin-dependent protein catabolic process;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
	This box: view; talk; edit;

　　[★]

英: presenilin-1
関: プレセニリン-1

「プレセニリン-1」

　　[★]

英: presenilin-1
関: プレセニリン1

[pmid1411576-1] Schellenberg GD, Bird TD, Wijsman EM, Orr HT, Anderson L, Nemens E, White JA, Bonnycastle L, Weber JL, Alonso ME, et al. (Nov 1992). "Genetic linkage evidence for a familial Alzheimer's disease locus on chromosome 14". Science 258 (5082): 668–71. Bibcode:1992Sci...258..668S. doi:10.1126/science.1411576. PMID 1411576.

[pmid22122073-2] St George-Hyslop P, Fraser PE (January 2012). "Assembly of the presenilin γ-/ε-secretase complex". J. Neurochem. 120 Suppl 1: 84–8. doi:10.1111/j.1471-4159.2011.07505.x. PMID 22122073.

[pmid7888181-3] Selkoe DJ (1994). "Cell biology of the amyloid beta-protein precursor and the mechanism of Alzheimer's disease". Annu. Rev. Cell Biol. 10: 373–403. doi:10.1146/annurev.cb.10.110194.002105. PMID 7888181.

[pmid16046406-4] Laudon H, Hansson EM, Melén K, Bergman A, Farmery MR, Winblad B, Lendahl U, von Heijne G, Näslund J (October 2005). "A nine-transmembrane domain topology for presenilin 1". J. Biol. Chem. 280 (42): 35352–60. doi:10.1074/jbc.M507217200. PMID 16046406.

[pmid18256384-5] Spasic D, Annaert W (February 2008). "Building gamma-secretase: the bits and pieces". J. Cell. Sci. 121 (Pt 4): 413–20. doi:10.1242/jcs.015255. PMID 18256384.

[Thinakaran_1996-6] Thinakaran G, Borchelt DR, Lee MK, Slunt HH, Spitzer L, Kim G, Ratovitsky T, Davenport F, Nordstedt C, Seeger M, Hardy J, Levey AI, Gandy SE, Jenkins NA, Copeland NG, Price DL, Sisodia SS (July 1996). "Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo". Neuron 17 (1): 181–90. doi:10.1016/S0896-6273(00)80291-3. PMID 8755489.

[pmid9305918-7] Ratovitski T, Slunt HH, Thinakaran G, Price DL, Sisodia SS, Borchelt DR (September 1997). "Endoproteolytic processing and stabilization of wild-type and mutant presenilin". J. Biol. Chem. 272 (39): 24536–41. doi:10.1074/jbc.272.39.24536. PMID 9305918.

[pmid10864326-8] Li YM, Xu M, Lai MT, Huang Q, Castro JL, DiMuzio-Mower J, Harrison T, Lellis C, Nadin A, Neduvelil JG, Register RB, Sardana MK, Shearman MS, Smith AL, Shi XP, Yin KC, Shafer JA, Gardell SJ (June 2000). "Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1". Nature 405 (6787): 689–94. doi:10.1038/35015085. PMID 10864326.

[pmid15866047-9] Brunkan AL, Martinez M, Walker ES, Goate AM (May 2005). "Presenilin endoproteolysis is an intramolecular cleavage". Mol. Cell. Neurosci. 29 (1): 65–73. doi:10.1016/j.mcn.2004.12.012. PMID 15866047.

[10] "Entrez Gene: PSEN1 presenilin 1 (Alzheimer disease 3)".

[pmid8878479-11] Duff K, Eckman C, Zehr C, Yu X, Prada CM, Perez-tur J, Hutton M, Buee L, Harigaya Y, Yager D, Morgan D, Gordon MN, Holcomb L, Refolo L, Zenk B, Hardy J, Younkin S (October 1996). "Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1". Nature 383 (6602): 710–3. Bibcode:1996Natur.383..710D. doi:10.1038/383710a0. PMID 8878479.

[pmid9450754-12] De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, Von Figura K, Van Leuven F (January 1998). "Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein". Nature 391 (6665): 387–90. Bibcode:1998Natur.391..387D. doi:10.1038/34910. PMID 9450754.

[pmid15087467-13] Pitsi D, Octave JN (June 2004). "Presenilin 1 stabilizes the C-terminal fragment of the amyloid precursor protein independently of gamma-secretase activity". J. Biol. Chem. 279 (24): 25333–8. doi:10.1074/jbc.M312710200. PMID 15087467.

[pmid12761548-14] Phiel CJ, Wilson CA, Lee VM, Klein PS (May 2003). "GSK-3alpha regulates production of Alzheimer's disease amyloid-beta peptides". Nature 423 (6938): 435–9. Bibcode:2003Natur.423..435P. doi:10.1038/nature01640. PMID 12761548.

[pmid9727485-15] Chan YM, Jan YN (August 1998). "Roles for proteolysis and trafficking in notch maturation and signal transduction". Cell 94 (4): 423–6. doi:10.1016/S0092-8674(00)81583-4. PMID 9727485.

[pmid9653148-16] Logeat F, Bessia C, Brou C, LeBail O, Jarriault S, Seidah NG, Israël A (July 1998). "The Notch1 receptor is cleaved constitutively by a furin-like convertase". Proc. Natl. Acad. Sci. U.S.A. 95 (14): 8108–12. Bibcode:1998PNAS...95.8108L. doi:10.1073/pnas.95.14.8108. PMC 20937. PMID 9653148.

[pmid9620803-17] Schroeter EH, Kisslinger JA, Kopan R (May 1998). "Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain". Nature 393 (6683): 382–6. Bibcode:1998Natur.393..382S. doi:10.1038/30756. PMID 9620803.

[pmid7566092-18] Jarriault S, Brou C, Logeat F, Schroeter EH, Kopan R, Israel A (September 1995). "Signalling downstream of activated mammalian Notch". Nature 377 (6547): 355–8. Bibcode:1995Natur.377..355J. doi:10.1038/377355a0. PMID 7566092.

[pmid10206646-19] Struhl G, Greenwald I (April 1999). "Presenilin is required for activity and nuclear access of Notch in Drosophila". Nature 398 (6727): 522–5. Bibcode:1999Natur.398..522S. doi:10.1038/19091. PMID 10206646.

[pmid10206645-20] De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, Schroeter EH, Schrijvers V, Wolfe MS, Ray WJ, Goate A, Kopan R (April 1999). "A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain". Nature 398 (6727): 518–22. Bibcode:1999Natur.398..518D. doi:10.1038/19083. PMID 10206645.

[Zhang_2009-21] Zhang C, Wu B, Beglopoulos V, Wines-Samuelson M, Zhang D, Dragatsis I, Südhof TC, Shen J (July 2009). "Presenilins are essential for regulating neurotransmitter release". Nature 460 (7255): 632–6. Bibcode:2009Natur.460..632Z. doi:10.1038/nature08177. PMC 2744588. PMID 19641596.

[Kang_2002-22] Kang DE, Soriano S, Xia X, Eberhart CG, De Strooper B, Zheng H, Koo EH (September 2002). "Presenilin couples the paired phosphorylation of beta-catenin independent of axin: implications for beta-catenin activation in tumorigenesis". Cell 110 (6): 751–62. doi:10.1016/S0092-8674(02)00970-4. PMID 12297048.

[pmid19383853-23] Su DM, Zhang Q, Wang X, He P, Zhu YJ, Zhao J, Rennert OM, Su YA (May 2009). "Two types of human malignant melanoma cell lines revealed by expression patterns of mitochondrial and survival-apoptosis genes: implications for malignant melanoma therapy". Mol. Cancer Ther. 8 (5): 1292–304. doi:10.1158/1535-7163.MCT-08-1030. PMC 3128982. PMID 19383853.

[pmid11902585-24] Gottesman MM, Fojo T, Bates SE (January 2002). "Multidrug resistance in cancer: role of ATP-dependent transporters". Nat. Rev. Cancer 2 (1): 48–58. doi:10.1038/nrc706. PMID 11902585.

[pmid22143792-25] Cho S, Lu M, He X, Ee PL, Bhat U, Schneider E, Miele L, Beck WT (December 2011). "Notch1 regulates the expression of the multidrug resistance gene ABCC1/MRP1 in cultured cancer cells". Proc. Natl. Acad. Sci. U.S.A. 108 (51): 20778–83. Bibcode:2011PNAS..10820778C. doi:10.1073/pnas.1019452108. PMID 22143792.

[pmid10521466-26] Alberici A, Moratto D, Benussi L, Gasparini L, Ghidoni R, Gatta LB, Finazzi D, Frisoni GB, Trabucchi M, Growdon JH, Nitsch RM, Binetti G (October 1999). "Presenilin 1 protein directly interacts with Bcl-2". J. Biol. Chem. 274 (43): 30764–9. doi:10.1074/jbc.274.43.30764. PMID 10521466.

[pmid9852041-27] Tesco G, Kim TW, Diehlmann A, Beyreuther K, Tanzi RE (December 1998). "Abrogation of the presenilin 1/beta-catenin interaction and preservation of the heterodimeric presenilin 1 complex following caspase activation". J. Biol. Chem. 273 (51): 33909–14. doi:10.1074/jbc.273.51.33909. PMID 9852041.

[pmid10341227-28] Kang DE, Soriano S, Frosch MP, Collins T, Naruse S, Sisodia SS, Leibowitz G, Levine F, Koo EH (June 1999). "Presenilin 1 facilitates the constitutive turnover of beta-catenin: differential activity of Alzheimer's disease-linked PS1 mutants in the beta-catenin-signaling pathway". J. Neurosci. 19 (11): 4229–37. PMID 10341227.

[pmid9738936-29] Murayama M, Tanaka S, Palacino J, Murayama O, Honda T, Sun X, Yasutake K, Nihonmatsu N, Wolozin B, Takashima A (August 1998). "Direct association of presenilin-1 with beta-catenin". FEBS Lett. 433 (1–2): 73–7. doi:10.1016/S0014-5793(98)00886-2. PMID 9738936.

[pmid10208590-30] Tanahashi H, Tabira T (February 1999). "Isolation of human delta-catenin and its binding specificity with presenilin 1". NeuroReport 10 (3): 563–8. doi:10.1097/00001756-199902250-00022. PMID 10208590.

[pmid9437013-31] Zhang W, Han SW, McKeel DW, Goate A, Wu JY (February 1998). "Interaction of presenilins with the filamin family of actin-binding proteins". J. Neurosci. 18 (3): 914–22. PMC 2042137. PMID 9437013.

[pmid12058025-32] Nielsen AL, Holm IE, Johansen M, Bonven B, Jørgensen P, Jørgensen AL (August 2002). "A new splice variant of glial fibrillary acidic protein, GFAP epsilon, interacts with the presenilin proteins". J. Biol. Chem. 277 (33): 29983–91. doi:10.1074/jbc.M112121200. PMID 12058025.

[pmid11719200-33] Annaert WG, Esselens C, Baert V, Boeve C, Snellings G, Cupers P, Craessaerts K, De Strooper B (November 2001). "Interaction with telencephalin and the amyloid precursor protein predicts a ring structure for presenilins". Neuron 32 (4): 579–89. doi:10.1016/S0896-6273(01)00512-8. PMID 11719200.

[pmid9771752-34] Buxbaum JD, Choi EK, Luo Y, Lilliehook C, Crowley AC, Merriam DE, Wasco W (October 1998). "Calsenilin: a calcium-binding protein that interacts with the presenilins and regulates the levels of a presenilin fragment". Nat. Med. 4 (10): 1177–81. doi:10.1038/2673. PMID 9771752.

[pmid10854253-35] Kashiwa A, Yoshida H, Lee S, Paladino T, Liu Y, Chen Q, Dargusch R, Schubert D, Kimura H (July 2000). "Isolation and characterization of novel presenilin binding protein". J. Neurochem. 75 (1): 109–16. doi:10.1046/j.1471-4159.2000.0750109.x. PMID 10854253.

[pmid15257293-36] Haffner C, Frauli M, Topp S, Irmler M, Hofmann K, Regula JT, Bally-Cuif L, Haass C (August 2004). "Nicalin and its binding partner Nomo are novel Nodal signaling antagonists". EMBO J. 23 (15): 3041–50. doi:10.1038/sj.emboj.7600307. PMC 514924. PMID 15257293.

[pmid14572442-37] Baulac S, LaVoie MJ, Kimberly WT, Strahle J, Wolfe MS, Selkoe DJ, Xia W (November 2003). "Functional gamma-secretase complex assembly in Golgi/trans-Golgi network: interactions among presenilin, nicastrin, Aph1, Pen-2, and gamma-secretase substrates". Neurobiol. Dis. 14 (2): 194–204. doi:10.1016/S0969-9961(03)00123-2. PMID 14572442.

[pmid12471034-38] Gu Y, Chen F, Sanjo N, Kawarai T, Hasegawa H, Duthie M, Li W, Ruan X, Luthra A, Mount HT, Tandon A, Fraser PE, St George-Hyslop P (February 2003). "APH-1 interacts with mature and immature forms of presenilins and nicastrin and may play a role in maturation of presenilin.nicastrin complexes". J. Biol. Chem. 278 (9): 7374–80. doi:10.1074/jbc.M209499200. PMID 12471034.

[pmid12297508-39] Lee SF, Shah S, Li H, Yu C, Han W, Yu G (November 2002). "Mammalian APH-1 interacts with presenilin and nicastrin and is required for intramembrane proteolysis of amyloid-beta precursor protein and Notch". J. Biol. Chem. 277 (47): 45013–9. doi:10.1074/jbc.M208164200. PMID 12297508.

[pmid10993067-40] Yu G, Nishimura M, Arawaka S, Levitan D, Zhang L, Tandon A, Song YQ, Rogaeva E, Chen F, Kawarai T, Supala A, Levesque L, Yu H, Yang DS, Holmes E, Milman P, Liang Y, Zhang DM, Xu DH, Sato C, Rogaev E, Smith M, Janus C, Zhang Y, Aebersold R, Farrer LS, Sorbi S, Bruni A, Fraser P, St George-Hyslop P (September 2000). "Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing". Nature 407 (6800): 48–54. doi:10.1038/35024009. PMID 10993067.

[pmid10092585-41] Stahl B, Diehlmann A, Südhof TC (April 1999). "Direct interaction of Alzheimer's disease-related presenilin 1 with armadillo protein p0071". J. Biol. Chem. 274 (14): 9141–8. doi:10.1074/jbc.274.14.9141. PMID 10092585.

[pmid11076969-42] Mah AL, Perry G, Smith MA, Monteiro MJ (November 2000). "Identification of ubiquilin, a novel presenilin interactor that increases presenilin protein accumulation". J. Cell Biol. 151 (4): 847–62. doi:10.1083/jcb.151.4.847. PMC 2169435. PMID 11076969.

匿名

検索

案内

案内

presenilin-1