Skip to main content

Presenilin

  • Reference work entry
  • First Online:
Encyclopedia of Signaling Molecules

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...

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 4,499.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 4,499.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Ballatore C, Lee VMY, Trojanowski JQ. Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci. 2007;8(9):663–72.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Beel AJ, Sanders CR. Substrate specificity of gamma-secretase and other intramembrane proteases. Cell Mol Life Sci. 2008;65(9):1311–34.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Brini M, Cali T, Ottolini D, Carafoli E. Neuronal calcium signaling: function and dysfunction. Cell Mol Life Sci. 2014;71(15):2787–814.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Duggan SP, McCarthy JV. Beyond gamma-secretase activity: the multifunctional nature of presenilins in cell signalling pathways. Cell Signal. 2016;28(1):1–11.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Freeman WJ. Alzheimer: the life of a physician and the career of a disease. Am J Psychiatry. 2004;161(2):381–2.

    Article  Google Scholar 

  • Gertsik N, Chiu D, Li YM. Complex regulation of gamma-secretase: from obligatory to modulatory subunits. Front Aging Neurosci. 2014;6:342.

    PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  Google Scholar 

  • Haapasalo A, Kovacs DM. The many substrates of presenilin/gamma-secretase. J Alzheimers Dis. 2011;25(1):3–28.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Nishitoh H. CHOP is a multifunctional transcription factor in the ER stress response. J Biochem. 2012;151(3):217–9.

    Article  CAS  PubMed  Google Scholar 

  • Nixon RA, Yang DS. Autophagy failure in Alzheimer’s disease-locating the primary defect. Neurobiol Dis. 2011;43(1):38–45.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Payne AJ, Kaja S, Koulen P. Regulation of ryanodine receptor-mediated calcium signaling by presenilins. Receptors Clin Investig. 2015;2(1):e449.

    PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Stiller I, Lizak B, Banhegyi G. Physiological functions of presenilins: beyond gamma-secretase. Curr Pharm Biotechnol. 2014;15(11):1019–25.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Tomita T, Tanaka S, Morohashi Y, Iwatsubo T. Presenilin-dependent intramembrane cleavage of ephrin-B1. Mol Neurodegener. 2006;1.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Zhang S, Zhang M, Cai F, Song W. Biological function of presenilin and its role in AD pathogenesis. Transl Neurodegener. 2013;2(1):15.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to I. Stiller .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG

About this entry

Check for updates. Verify currency and authenticity via CrossMark

Cite this entry

Stiller, I., Valdinger, A., Banhegyi, G. (2018). Presenilin. In: Choi, S. (eds) Encyclopedia of Signaling Molecules. Springer, Cham. https://doi.org/10.1007/978-3-319-67199-4_101796

Download citation

Publish with us

Policies and ethics