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Presenilin-1

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Presenilin-1 (PS-1) is a presenilin protein that in humans is encoded by the PSEN1 gene.[5] Presenilin-1 is one of the four core proteins in the gamma secretase complex, which is considered to play an important role in generation of amyloid beta (Aβ) from amyloid-beta precursor protein (APP). Accumulation of amyloid beta is associated with the onset of Alzheimer's disease.[6]

PSEN1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesPSEN1, Psen1, Ad3h, PS-1, PS1, S182, AD3, FAD, presenilin 1, ACNINV3
External IDsOMIM: 104311; MGI: 1202717; HomoloGene: 7186; GeneCards: PSEN1; OMA:PSEN1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

5663

19164

Ensembl

ENSG00000080815

ENSMUSG00000019969

UniProt

P49768

P49769

RefSeq (mRNA)

NM_000021
NM_007318
NM_007319

NM_008943
NM_001362271

RefSeq (protein)

NP_000012
NP_015557

NP_001349200

Location (UCSC)Chr 14: 73.14 – 73.22 MbChr 12: 83.73 – 83.78 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Structure

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Presenilin possesses a 9 transmembrane domain topology, with an extracellular C-terminus and a cytosolic N-terminus.[7][8] Presenilin undergoes endo-proteolytic processing to produce ~27-28 kDa N-terminal and ~16-17 kDa C-terminal fragments in humans.[9] Furthermore, presenilin exists in the cell mainly as a heterodimer of the C-terminal and N-terminus fragments.[9] When presenilin 1 is overexpressed, the full length protein accumulates in an inactive form.[10] Based on evidence that a gamma-secretase inhibitor binds to the fragments,[11] the cleaved presenilin complex is considered to be the active form.[12]

Function

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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.[13]

Notch signaling pathway

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In Notch signaling, critical proteolytic reactions takes place during maturation and activation of Notch membrane receptor.[14] Notch1 is cleaved extracellularlly at site1 (S1) and two polypeptides are produced to form a heterodimer receptor on the cell surface.[15] After the formation of receptor, Notch1 is further cleaved in site 3(S3)[16] and release Notch1 intracellular domain (NICD) from the membrane.[17]

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.[18] 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.[19] These evidences collectively suggest a critical role of presenilin 1 in the Notch signaling pathway.

Wnt signaling pathway

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Wnt signaling pathway has been shown to be involved in several critical steps in embryogenesis and development. Presenilin 1 has been shown to form a complex with beta-catenin, an important component in Wnt signaling, and stabilize beta-catenin.[20] Mutant of presenilin-1 that reduces the ability to stabilize beta-catenin complex leads to hyperactive degradation of beta-catenin in the brains of transgenic mice.[20]

Considered as a negative regulator in wnt signaling pathway, presenilin-1 was also found to play a role in beta-catenin phosphorylation.[21] Beta-catenin is coupled by presenilin-1 and undergoes a sequential phosphorylation by two kinase activities.[21] The study also further illustrates that the deficiency of presenilin 1 disconnects the sequential phosphorylation and thus disrupts the normal wnt signaling pathway.[21]

Clinical significance

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Beta-amyloid production

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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.[22] Further study conducted in neuronal cultures derived from presenilin-1 deficient mouse embryos showed that cleavage by alpha- and beta- secretase was still normal without the presence of presenilin-1. Meanwhile, when 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 downregulate amyloid and inhibition of presenilin-1 can be a potential method for anti-amyloidogenic therapy in Alzheimer's disease.[23] Extensive study on the role of presenilin-1 in amyloid production has been conducted to improve our understanding of Alzheimer's disease.[24][25]

Alzheimer's disease

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Alzheimer's disease (AD) patients with an inherited form of the disease may 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). These mutations result in early-onset Alzheimer's Disease, which is a rare form of the disease. These rare genetic variants are autosomal dominant.[26]

Cancer

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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 this cell type while it is overexpressed in the other cell type.[27] 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 chemicals, MDR cells become a critical factor on the success of cancer chemotherapy.[28] In the study, researchers 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 proteins 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.[29]

Interactions

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PSEN1 has been shown to interact with:

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000080815 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000019969 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Schellenberg GD, Bird TD, Wijsman EM, Orr HT, Anderson L, Nemens E, White JA, Bonnycastle L, Weber JL, Alonso ME (Nov 1992). "Genetic linkage evidence for a familial Alzheimer's seasesease locus on chromosome 14". Science. 258 (5082): 668–71. Bibcode:1992Sci...258..668S. doi:10.1126/science.1411576. PMID 1411576.
  6. ^ 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.
  7. ^ 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.
  8. ^ 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.
  9. ^ 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.
  10. ^ 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.
  11. ^ 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. Bibcode:2000Natur.405..689L. doi:10.1038/35015085. PMID 10864326. S2CID 4420032.
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  23. ^ 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. S2CID 4397720.
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  25. ^ 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. S2CID 4416851.
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  27. ^ 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.
  28. ^ 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. S2CID 34650170.
  29. ^ 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. PMC 3251103. PMID 22143792.
  30. ^ 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.
  31. ^ 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.
  32. ^ 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. doi:10.1523/JNEUROSCI.19-11-04229.1999. PMC 6782616. PMID 10341227.
  33. ^ 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. S2CID 85416623.
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  35. ^ 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. doi:10.1523/JNEUROSCI.18-03-00914.1998. PMC 2042137. PMID 9437013.
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  45. ^ 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. Bibcode:2000Natur.407...48Y. doi:10.1038/35024009. PMID 10993067. S2CID 4339220.
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  47. ^ 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.

Further reading

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