Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


  • I. StillerEmail author
  • A. Valdinger
  • G. Banhegyi
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101796

Historical Background

Presenilins (PSs) were first identified in early 1990s as multipass transmembrane proteins those mutations causing familial early-onset forms of Alzheimer disease in which symptoms usually develop between a person’s early 40s and mid-50s. Alzheimer’s disease (AD), as the most common form of dementia, is a major public health problem in the world especially in developed country. Presenilins, the core units of the γ -secretase complex, participate in the process of amyloid beta protein (Aβ) that plays central role in the pathogenesis of AD. However, there are numerous pieces of evidence that PS mutations have several γ -secretase-independent effects.

Presenilins and γ-Secretase Assembly

PSs are highly conserved transmembrane proteins with aspartyl protease activity, characterized by nine helical transmembrane domains (TMD). In mammals, two homologs are present: PS1 and PS2. The homology between them is about 67%. PSs are mostly localized in the ER, Golgi, and in...

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  1. Avrahami L, Farfara D, Shaham-Kol M, Vassar R, Frenkel D, Eldar-Finkelman H. Inhibition of glycogen synthase kinase-3 ameliorates beta-amyloid pathology and restores lysosomal acidification and mammalian target of rapamycin activity in the Alzheimer disease mouse model. J Biol Chem. 2013;288(2):1295–306.CrossRefPubMedGoogle Scholar
  2. Ballatore C, Lee VMY, Trojanowski JQ. Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci. 2007;8(9):663–72.CrossRefPubMedGoogle Scholar
  3. Banhegyi G, Baumeister P, Benedetti A, Dong D, Fu Y, Lee AS, et al. Endoplasmic reticulum stress. Ann NY Acad Sci. 2007;1113:58–71.CrossRefPubMedGoogle Scholar
  4. Beel AJ, Sanders CR. Substrate specificity of gamma-secretase and other intramembrane proteases. Cell Mol Life Sci. 2008;65(9):1311–34.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Brini M, Cali T, Ottolini D, Carafoli E. Neuronal calcium signaling: function and dysfunction. Cell Mol Life Sci. 2014;71(15):2787–814.CrossRefPubMedGoogle Scholar
  6. Cataldo AM, Peterhoff CM, Schmidt SD, Terio NB, Duff K, Beard M, et al. Presenilin mutations in familial Alzheimer disease and transgenic mouse models accelerate neuronal lysosomal pathology. J Neuropathol Exp Neurol. 2004;63(8):821–30.CrossRefPubMedGoogle Scholar
  7. Cheung KH, Shineman D, Muller M, Cardenas C, Mei L, Yang J, et al. Mechanism of Ca2+ disruption in Alzheimer’s disease by presenilin regulation of InsP3 receptor channel gating. Neuron. 2008;58(6):871–83.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Cheung KH, Mei L, Mak DO, Hayashi I, Iwatsubo T, Kang DE, et al. Gain-of-function enhancement of IP3 receptor modal gating by familial Alzheimer’s disease-linked presenilin mutants in human cells and mouse neurons. Sci Signal. 2010;3(114):ra22.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Coen K, Flannagan RS, Baron S, Carraro-Lacroix LR, Wang D, Vermeire W, et al. Lysosomal calcium homeostasis defects, not proton pump defects, cause endo-lysosomal dysfunction in PSEN-deficient cells. J Cell Biol. 2012;198(1):23–35.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Duan LS, Bhattacharyya BJ, Belmadani A, Pan LL, Miller RJ, Kessler JA. Stem cell derived basal forebrain cholinergic neurons from Alzheimer’s disease patients are more susceptible to cell death. Mol Neurodegener. 2014;9:3.PubMedPubMedCentralCrossRefGoogle Scholar
  11. Duggan SP, McCarthy JV. Beyond gamma-secretase activity: the multifunctional nature of presenilins in cell signalling pathways. Cell Signal. 2016;28(1):1–11.CrossRefPubMedGoogle Scholar
  12. Esselens C, Oorschot V, Baert V, Raemaekers T, Spittaels K, Serneels L, et al. Presenilin 1 mediates the turnover of telencephalin in hippocampal neurons via an autophagic degradative pathway. J Cell Biol. 2004;166(7):1041–54.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Francis R, McGrath G, Zhang JH, Ruddy DA, Sym M, Apfeld J, et al. aph-1 and pen-2 are required for notch pathway signaling, gamma-secretase cleavage of beta APP, and presenilin protein accumulation. Dev Cell. 2002;3(1):85–97.CrossRefPubMedGoogle Scholar
  14. Freeman WJ. Alzheimer: the life of a physician and the career of a disease. Am J Psychiatry. 2004;161(2):381–2.CrossRefGoogle Scholar
  15. Gertsik N, Chiu D, Li YM. Complex regulation of gamma-secretase: from obligatory to modulatory subunits. Front Aging Neurosci. 2014;6:342.PubMedGoogle Scholar
  16. Ghavami S, Shojaeid S, Yeganeh B, Ande SR, Jangamreddy JR, Mehrpour M, et al. Autophagy and apoptosis dysfunction in neurodegenerative disorders. Prog Neurobiol. 2014;112:24–49.CrossRefPubMedGoogle Scholar
  17. Green KN, Demuro A, Akbari Y, Hitt BD, Smith IF, Parker I, et al. SERCA pump activity is physiologically regulated by presenilin and regulates amyloid beta production. J Cell Biol. 2008;181(7):1107–16.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Haapasalo A, Kovacs DM. The many substrates of presenilin/gamma-secretase. J Alzheimers Dis. 2011;25(1):3–28.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Holczer M, Marton M, Kurucz A, Banhegyi G, Kapuy O. A comprehensive systems biological study of autophagy-apoptosis crosstalk during endoplasmic reticulum stress. Biomed Res Int. 2015;2015:319589.PubMedPubMedCentralCrossRefGoogle Scholar
  20. Jin HF, Sanjo N, Uchihara T, Watabe K, St George-Hyslop P, Fraser PE, et al. Presenilin-1 holoprotein is an interacting partner of sarco endoplasmic reticulum calcium-ATPase and confers resistance to endoplasmic reticulum stress. J Alzheimers Dis. 2010;20(1):261–73.CrossRefPubMedGoogle Scholar
  21. Katayama T, Imaizumi K, Sato N, Miyoshi K, Kudo T, Hitomi J, et al. Presenilin-1 mutations downregulate the signalling pathway of the unfolded-protein response. Nat Cell Biol. 1999;1(8):479–85.CrossRefPubMedGoogle Scholar
  22. Lai MT, Chen E, Crouthamel MC, DiMuzio-Mower J, Xu M, Huang Q, et al. Presenilin-1 and presenilin-2 exhibit distinct yet overlapping gamma-secretase activities. J Biol Chem. 2003;278(25):22475–81.CrossRefPubMedGoogle Scholar
  23. Lee JH, Yu WH, Kumar A, Lee S, Mohan PS, Peterhoff CM, et al. Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell. 2010;141(7):1146–58.PubMedPubMedCentralCrossRefGoogle Scholar
  24. Levitan D, Doyle TG, Brousseau D, Lee MK, Thinakaran G, Slunt HH, et al. Assessment of normal and mutant human presenilin function in Caenorhabditis elegans. Proc Natl Acad Sci USA. 1996;93(25):14940–4.PubMedPubMedCentralCrossRefGoogle Scholar
  25. Li Y, Bohm C, Dodd R, Chen FS, Qamar S, Schmitt-Ulms G, et al. Structural biology of presenilin 1 complexes. Mol Neurodegener. 2014;9:59.PubMedPubMedCentralCrossRefGoogle Scholar
  26. Mak DO, Cheung KH, Toglia P, Foskett JK, Ullah G. Analyzing and quantifying the gain-of-function enhancement of IP3 receptor gating by familial Alzheimer’s disease-causing mutants in presenilins. PLoS Comput Biol. 2015;11(10):e1004529.PubMedPubMedCentralCrossRefGoogle Scholar
  27. Nishitoh H. CHOP is a multifunctional transcription factor in the ER stress response. J Biochem. 2012;151(3):217–9.CrossRefPubMedGoogle Scholar
  28. Nixon RA, Yang DS. Autophagy failure in Alzheimer’s disease-locating the primary defect. Neurobiol Dis. 2011;43(1):38–45.PubMedPubMedCentralCrossRefGoogle Scholar
  29. Parent AT, Barnes NY, Taniguchi Y, Thinakaran G, Sisodia SS. Presenilin attenuates receptor-mediated signaling and synaptic function. J Neurosci. 2005;25(6):1540–9.CrossRefPubMedGoogle Scholar
  30. Payne AJ, Gerdes BC, Naumchuk Y, McCalley AE, Kaja S, Koulen P. Presenilins regulate the cellular activity of ryanodine receptors differentially through isotype-specific N-terminal cysteines. Exp Neurol. 2013;250:143–50.CrossRefPubMedGoogle Scholar
  31. Payne AJ, Kaja S, Koulen P. Regulation of ryanodine receptor-mediated calcium signaling by presenilins. Receptors Clin Investig. 2015;2(1):e449.PubMedPubMedCentralGoogle Scholar
  32. Sardi SP, Murtie J, Koirala S, Patten BA, Corfas G. Presenilin-dependent ErbB4 nuclear signaling regulates the timing of astrogenesis in the developing brain. Cell. 2006;127(1):185–97.CrossRefPubMedGoogle Scholar
  33. Song WH, Nadeau P, Yuan ML, Yang XD, Shen J, Yankner BA. Proteolytic release and nuclear translocation of Notch-1 are induced by presenilin-1 and impaired by pathogenic presenilin-1 mutations. Proc Natl Acad Sci USA. 1999;96(12):6959–63.PubMedPubMedCentralCrossRefGoogle Scholar
  34. Stiller I, Lizak B, Banhegyi G. Physiological functions of presenilins: beyond gamma-secretase. Curr Pharm Biotechnol. 2014;15(11):1019–25.CrossRefPubMedGoogle Scholar
  35. Szaraz P, Banhegyi G, Marcolongo P, Benedetti A. Transient knockdown of presenilin-1 provokes endoplasmic reticulum stress related formation of autophagosomes in HepG2 cells. Arch Biochem Biophys. 2013;538(2):57–63.CrossRefPubMedGoogle Scholar
  36. Teranishi Y, Inoue M, Yamamoto NG, Kihara T, Wiehager B, Ishikawa T, et al. Proton myo-inositol cotransporter is a novel gamma-secretase associated protein that regulates Abeta production without affecting Notch cleavage. FEBS J. 2015;282(17):3438–51.CrossRefPubMedGoogle Scholar
  37. Tomita T, Tanaka S, Morohashi Y, Iwatsubo T. Presenilin-dependent intramembrane cleavage of ephrin-B1. Mol Neurodegener. 2006;1.PubMedPubMedCentralCrossRefGoogle Scholar
  38. Volosin M, Song WY, Almeida RD, Kaplan DR, Hempstead BL, Friedman WJ. Interaction of survival and death signaling in basal forebrain neurons: roles of neurotrophins and proneurotrophins. J Neurosci. 2006;26(29):7756–66.CrossRefPubMedGoogle Scholar
  39. Wolfe DM, Lee JH, Kumar A, Lee S, Orenstein SJ, Nixon RA. Autophagy failure in Alzheimer’s disease and the role of defective lysosomal acidification. Eur J Neurosci. 2013;37(12):1949–61.PubMedPubMedCentralCrossRefGoogle Scholar
  40. Wong PC, Zheng H, Chen H, Becher MW, Sirinathsinghji DJS, Trumbauer ME, et al. Presenilin 1 is required for Notch1 DII1 expression in the paraxial mesoderm. Nature. 1997;387(6630):288–92.CrossRefPubMedGoogle Scholar
  41. Yoshimori T, Yamamoto A, Moriyama Y, Futai M, Tashiro Y. Bafilomycin-A1, a specific inhibitor of vacuolar-type H+−Atpase, inhibits acidification and protein-degradation in lysosomes of cultured-cells. J Biol Chem. 1991;266(26):17707–12.PubMedGoogle Scholar
  42. Yuan X, Wu H, Xu HX, Xiong HH, Chu Q, Yu SY, et al. Notch signaling: an emerging therapeutic target for cancer treatment. Cancer Lett. 2015;369(1):20–7.CrossRefPubMedPubMedCentralGoogle Scholar
  43. Zhang S, Zhang M, Cai F, Song W. Biological function of presenilin and its role in AD pathogenesis. Transl Neurodegener. 2013;2(1):15.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Medical Chemistry, Molecular Biology and PathobiochemistrySemmelweis UniversityBudapestHungary