Skip to main content
Log in

Metabolism of Presenilins

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Understanding mechanisms involved in the production of Aβ has long been the central focus of cell biologists engaged in molecular AD research. The discovery of two genes that encode homologous polytopic membrane proteins termed Presenilins (PS), has lead to several exciting recent findings on the proteolytic processes responsible for generating the COOH-terminus of Aβ. What we now know is that PS proteins play an important role in Aβ production and are considered one of the therapeutic targets. Here I have reviewed the vast literature on the biology of PS, especially focusing on PS endoproteolysis and the accumulation of stable PS derivatives that are likely the functional units.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Borchelt D. R., Thinakaran G., Eckman C. B., Lee M. K., Davenport F., Ratovitsky T., et al. (1996) Familial Alzheimer’s disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo. Neuron 17, 1005–1013.

    Article  PubMed  CAS  Google Scholar 

  • Brockhaus M., Grunberg J., Rohrig S., Loetscher H., Wittenburg N., Baumeister R., et al. (1998) Caspasemediated cleavage is not required for the activity of presenilins in amyloidogenesis and NOTCH signaling. Neuroreport 9, 1481–1486.

    Article  PubMed  CAS  Google Scholar 

  • Capell A., Grunberg J., Pesold B., Diehlmann A., Citron M., Nixon R., et al. (1998) The proteolytic fragments of the Alzheimer’s disease-associated presenilin-1 form heterodimers and occur as a 100–150-kDa molecular mass complex. J. Biol. Chem. 273, 3205–3211.

    Article  PubMed  CAS  Google Scholar 

  • Capell A., Saffrich R., Olivo J. C., Meyn L., Walter J., Grunberg J., et al. (1997) Cellular expression and proteolytic processing of presenilin proteins is developmentally regulated during neuronal differentiation. J. Neurochem. 69, 2432–2440.

    Article  PubMed  CAS  Google Scholar 

  • Capell A., Steiner H., Romig H., Keck S., Baader M., Grim M. G., et al. (2000) Presenilin-1 differentially facilitates endoproteolysis of the beta-amyloid precursor protein and Notch. Nat. Cell Biol. 2, 205–211.

    Article  PubMed  CAS  Google Scholar 

  • Citron M., Westaway D., Xia W., Carlson G., Diehl T., Levesque G., et al. (1997) Mutant presenilins of Alzheimer’s disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice. Nature Med. 3, 67–72.

    Article  PubMed  CAS  Google Scholar 

  • Duff K., Eckman C., Zehr C., Yu X., Prada C. M., Pereztur J., et al. (1996) Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature 383, 710–713.

    Article  PubMed  CAS  Google Scholar 

  • Esler W. P., Kimberly W. T., Ostaszewski B. L., Diehl T. S., Moore C. L., Tsai J. Y., et al. (2000) Transition-state analogue inhibitors of gamma-secretase bind directly to presenilin-1. Nat. Cell Biol. 2, 428–434.

    Article  PubMed  CAS  Google Scholar 

  • Fraser P. E., Levesque G., Yu G., Mills L. R., Thirlwell J., Frantseva M., et al. (1998) Presenilin 1 is actively degraded by the 26S proteasome. Neurobiol Aging 19, S19-S21.

    Article  PubMed  CAS  Google Scholar 

  • Goutte C., Hepler W., Mickey K. M., and Priess J. R. (2000) aph-2 encodes a novel extracellular protein required for GLP-1-mediated signaling. Development 127, 2481–2492.

    PubMed  CAS  Google Scholar 

  • Grunberg J., Walter J., Loetscher H., Deuschle U., Jacobsen H., and Haass C. (1998) Alzheimer’s disease associated presenilin-1 holoprotein and its 18–20 kDa C-terminal fragment are death substrates for proteases of the caspase family. Biochemistry 37, 2263–2270.

    Article  PubMed  CAS  Google Scholar 

  • Guo Y., Livne-Bar I., Zhou L., and Boulianne G. L. (1999) Drosophila presenilin is required for neuronal differentiation and affects notch subcellular localization and signaling. J. Neurosci. 19, 8435–8442.

    PubMed  CAS  Google Scholar 

  • Hartmann H., Busciglio J., Baumann K. H., Staufenbiel M., and Yankner B. A. (1997) Developmental regulation of presenilin-1 processing in the brain suggests a role in neuronal differentiation. J. Biol. Chem. 272, 14,505–14,508.

    Article  CAS  Google Scholar 

  • Hendriks L., Thinakaran G., Harris C. L., De Jonghe C., Martin J. J., Sisodia S. S., and Van Broeckhoven C. (1997) Processing of presenilin 1 in brains of patients with Alzheimer’s disease and controls. Neuroreport 8, 1717–1721.

    Article  PubMed  CAS  Google Scholar 

  • Honda T., Yasutake K., Nihonmatsu N., Mercken M., Takahashi H., Murayama O., et al. (1999) Dual roles of proteasome in the metabolism of presenilin 1. J. Neurochem. 72, 255–261.

    Article  PubMed  CAS  Google Scholar 

  • Jacobsen H., Reinhardt D., Brockhaus M., Bur D., Kocyba C., Kurt H., et al. (1999) The influence of endoproteolytic processing of familial Alzheimer’s disease presenilin 2 on abeta42 amyloid peptide formation. J. Biol. Chem. 274, 35,233–35,239.

    CAS  Google Scholar 

  • Kang D. E., Soriano S., Frosch M. P., Collins T., Naruse S., Sisodia S. S., et al. (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, 4229–4237.

    PubMed  CAS  Google Scholar 

  • Kim T. W., Pettingell W. H., Hallmark O. G., Moir R. D., Wasco W., and Tanzi R. E. (1997a) Endoproteolytic cleavage and proteasomal degradation of presenilin 2 in transfected cells. J. Biol. Chem. 272, 11,006–11,010.

    CAS  Google Scholar 

  • Kim T. W., Pettingell W. H., Jung Y. K., Kovacs D. M., and Tanzi R. E. (1997b) Alternative cleavage of Alzheimer-associated presenilins during apoptosis by a caspase-3 family protease. Science 277, 373–376.

    Article  PubMed  CAS  Google Scholar 

  • Kimberly W. T., Xia W., Rahmati T., Wolfe M. S., and Selkoe D. J. (2000) The transmembrane aspartates in presenilin 1 and 2 are obligatory for gamma-secretase activity and amyloid beta-protein generation. J. Biol. Chem. 275, 3173–3178.

    Article  PubMed  CAS  Google Scholar 

  • Lau K. F., McLoughlin D. M., Standen C., and Miller C. C. (2000) X11 alpha and x11 beta interact with presenilin-1 via their PDZ domains. Mol. Cell Neurosci. 16, 557–565.

    Article  PubMed  CAS  Google Scholar 

  • Leimer U., Lun K., Romig H., Walter J., Grunberg J., Brand M., and Haass C. (1999) Zebrafish (Danio rerio) presenilin promotes aberrant amyloid beta- peptide production and requires a critical aspartate residue for its function in amyloidogenesis. Biochemistry 38, 13,602–13,609.

    Article  CAS  Google Scholar 

  • Levitan D., Doyle T. G., Brousseau D., Lee M. K., Thinakaran G., Slunt H. H., et al. (1996) Assessment of normal and mutant human presenilin function in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 93, 14,940–14,944.

    Article  CAS  Google Scholar 

  • Lewis P. A., Perez-Tur J., Golde T. E., and Hardy J. (2000) The presenilin 1 C92S mutation increases abeta 42 production. Biochem. Biophys. Res. Comm. 277, 261–263.

    Article  PubMed  CAS  Google Scholar 

  • Li X. and Greenwald I. (1996) Membrane topology of the C. elegans SEL-12 presenilin. Neuron 17, 1015–1021.

    Article  PubMed  CAS  Google Scholar 

  • Li Y. M., Xu M., Lai M. T., Huang Q., Castro J. L., DiMuzio-Mower J., et al. (2000) Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1. Nature 405, 689–694.

    Article  PubMed  CAS  Google Scholar 

  • Loetscher H., Deuschle U., Brockhaus M., Reinhardt D., Nelboeck P., Mous J., et al. (1997) Presenilins are processed by caspase-type proteases. J. Biol. Chem. 272, 20,655–20,659.

    Article  CAS  Google Scholar 

  • Mercken M., Takahashi H., Honda T., Sato K., Murayama M., Nakazato Y., et al. (1996) Characterization of human presenilin 1 using N-terminal specific monoclonal antibodies: evidence that Alzheimer mutations affect proteolytic processing. FEBS Lett. 389, 297–303.

    Article  PubMed  CAS  Google Scholar 

  • Morihara T., Katayama T., Sato N., Yoneda T., Manabe T., Hitomi J., et al. (2000) Absence of endoproteolysis but no effects on amyloid beta production by alternative splicing forms of presenilin-1, which lack exon 8 and replace D257A. Brain Res. Mol. Brain Res. 85, 85–90.

    Article  PubMed  CAS  Google Scholar 

  • Murayama O., Honda T., Mercken M., Murayama M., Yasutake K., Nihonmatsu N., et al. (1997) Different effects of Alzheimer-associated mutations of presenilin 1 on its processing. Neurosci. Lett. 229, 61–64.

    Article  PubMed  CAS  Google Scholar 

  • Nakano Y., Kondoh G., Kudo T., Imaizumi K., Kato M., Miyazaki J. I., et al. (1999) Accumulation of murine amyloidbeta42 in a gene-dosage-dependent manner in PS1 ‘knock-in’ mice. Eur. J. Neurosci. 11, 2577–2581.

    Article  PubMed  CAS  Google Scholar 

  • Nishimura M., Yu G., Levesque G., Zhang D. M., Ruel L., Chen F., et al. (1999) Presenilin mutations associated with Alzheimer disease cause defective intracellular trafficking of beta-catenin, a component of the presenilin protein complex. Nature Med. 5, 164–169.

    Article  PubMed  CAS  Google Scholar 

  • Nowotny P., Gorski S. M., Han S. W., Philips K., Ray W. J., Nowotny V., et al. (2000) Posttranslational modification and plasma membrane localization of the Drosophila melanogaster presenilin. Mol. Cell Neurosci. 15, 88–98.

    Article  PubMed  CAS  Google Scholar 

  • Okochi M., Eimer S., Bottcher A., Baumeister R., Romig H., Walter J., et al. (2000) A loss of function mutant of the presenilin homologue sel-12 undergoes abberant endoproteolysis in Caenorhabditis elegans and increased A-beta-42 generation in human cells. J. Biol. Chem. 275, 40,925–40,932.

    CAS  Google Scholar 

  • Okochi M., Ishii K., Usami M., Sahara N., Kametani F., Tanaka K., et al. (1997) Proteolytic processing of presenilin-1 (PS-1) is not associated with Alzheimer’s disease with or without PS-1 mutations. FEBS Lett. 418, 162–166.

    Article  PubMed  CAS  Google Scholar 

  • Oyama F., Sawamura N., Kobayashi K., Morishima-Kawashima M., Kuramochi T., Ito M., et al. (1998) Mutant presenilin 2 transgenic mouse: effect on an age-dependent increase of amyloid beta-protein 42 in the brain. J. Neurochem. 71, 313–322.

    Article  PubMed  CAS  Google Scholar 

  • Passer B. J., Pellegrini L., Vito P., Ganjei J. K., and D’Adamio L. (1999) Interaction of Alzheimer’s presenilin-1 and presenilin-2 with Bcl-X(L). A potential role in modulating the threshold of cell death. J. Biol. Chem. 274, 24,007–24,013.

    Article  CAS  Google Scholar 

  • Podlisny M. B., Citron M., Amarante P., Sherrington R., Xia W., Zhang J., et al. (1997) Presenilin proteins undergo heterogeneous endoproteolysis between Thr291 and Ala299 and occur as stable N- and C-terminal fragments in normal and Alzheimer brain tissue. Neurobiol. Dis. 3, 325–337.

    Article  PubMed  CAS  Google Scholar 

  • Ratovitski T., Slunt H. H., Thinakaran G., Price D. L., Sisodia S. S., and Borchelt D. R. (1997) Endoproteolytic processing and stabilization of wild-type and mutant presenilin. J. Biol. Chem. 272, 24,536–24,541.

    Article  CAS  Google Scholar 

  • Sato N., Urano F., Leem J. Y., Kim S.-H., Li M., Donoviel D., Bernstein A., et al. (2000) Upregulation of BiP and CHOP by the unfolded-protein response is independent of presenilin expression. Nature Cell Biol. 2, 863–870.

    Article  PubMed  CAS  Google Scholar 

  • Saura C. A., Tomita T., Davenport F., Harris C. L., Iwatsubo T., and Thinakaran G. (1999) Evidence that intramolecular associations between Presenilin domains are obligatory for endoproteolytic processing. J. Biol. Chem. 274, 13,818–13,823.

    Article  CAS  Google Scholar 

  • Saura C. A., Tomita T., Soriano S., Takahashi M., Leem J. Y., Honda T., et al. (2000) The non-conserved hydrophilic loop domain of presenilin (PS) is neither required for PS endoproteolysis nor enhanced Aβ42 production mediated by familial Alzheimer’s disease-linked PS variants. J. Biol. Chem. 275, 17,136–17,142.

    Article  CAS  Google Scholar 

  • Seeger M., Nordstedt C., Petanceska S., Kovacs D. M., Gouras G. K., Hahne S., et al. (1997) Evidence for phosphorylation and oligomeric assembly of presenilin 1. Proc. Natl. Acad. Sci. USA 94, 5090–5094.

    Article  PubMed  CAS  Google Scholar 

  • Shirotani K., Takahashi K., Araki W., Maruyama K., and Tabira T. (2000) Mutational analysis of intrinsic regions of presenilin 2 that determine its endoproteolytic cleavage and pathological function. J. Biol. Chem. 275, 3681–3686.

    Article  PubMed  CAS  Google Scholar 

  • Shirotani K., Takahashi K., Ozawa K., Kunishita T., and Tabira T. (1997) Determination of a cleavage site of presenilin 2 protein in stably transfected SH-SY5Y human neuroblastoma cell lines. Biochem. Biophys. Res. Comm. 240, 728–731.

    Article  PubMed  CAS  Google Scholar 

  • Shirotani K., Takahashi K., and Tabira T. (1999) Effects of presenilin N-terminal fragments on production of amyloid beta peptide and accumulation of endogenous presenilins. Neurosci. Lett. 262, 37–40.

    Article  PubMed  CAS  Google Scholar 

  • Song S., Ohba M., Saito Y., Honda T., Takashima A., and Takahashi H. (2000) Proteolytic processing and degradation of human presenilin-1 expressed in yeast. Neurosci. Lett. 282, 65–68.

    Article  PubMed  CAS  Google Scholar 

  • Soriano S., Kang D. E., Fu M., Pestell R., Chevallier N., Zheng H., and Koo E. H. (2001) Presenilin 1 negatively regulates beta-catenin/T cell factor/lymphoid enhancer factor-1 signaling independently of beta-amyloid precursor protein and notch processing. J. Cell Biol. 152, 785–794.

    Article  PubMed  CAS  Google Scholar 

  • Steiner H., Capell A., Pesold B., Citron M., Kloetzel P. M., Selkoe D. J., et al. (1998) Expression of Alzheimer’s disease-associated presenilin-1 is controlled by proteolytic degradation and complex formation. J. Biol. Chem. 273, 32,322–32,331.

    Article  CAS  Google Scholar 

  • Steiner H., Kostka M., Romig H., Basset G., Pesold B., Hardy J., et al. (2000) Glycine 384 is required for presenilin-1 function and is conserved in bacterial polytopic aspartyl proteases. Nat. Cell Biol. 2, 848–851.

    Article  PubMed  CAS  Google Scholar 

  • Steiner H., Romig H., Pesold B., Philipp U., Baader M., Citron M., et al. (1999) Amyloidogenic function of the Alzheimer’s disease-associated presenilin 1 in the absence of endoproteolysis. Biochemistry 38, 14,600–14,605.

    Article  CAS  Google Scholar 

  • Takahashi H., Mercken M., Honda T., Saito Y., Murayama M., Song S., and Takashima A. (1999) Impaired proteolytic processing of presenilin-1 in chromosome 14-linked familial Alzheimer’s disease patient lymphocytes. Neurosci. Lett. 260, 121–124.

    Article  PubMed  CAS  Google Scholar 

  • Thinakaran G., Borchelt D. R., Lee M. K., Slunt H. H., Spitzer L., Kim G., et al. (1996) Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron 17, 181–190.

    Article  PubMed  CAS  Google Scholar 

  • Thinakaran G., Harris C. L., Ratovitski T., Davenport F., Slunt H. H., Price D. L., et al. (1997) Evidence that levels of presenilins (PS1 and PS2) are coordinately regulated by competition for limiting cellular factors. J. Biol. Chem. 272, 28,415–28,422.

    Article  CAS  Google Scholar 

  • Thinakaran G., Regard J. B., Bouton C. M. L., Harris C. L., Price D. L., Borchelt D. R., and Sisodia S. S. (1998) Stable association of presenilin derivatives and absence of presenilin interactions with APP. Neurobiol. Dis. 4, 438–453.

    Article  PubMed  CAS  Google Scholar 

  • Tomidokoro Y., Ishiguro K., Igeta Y., Matsubara E., Kanai M., Shizuka M., et al. (1999) Carboxyl-terminal fragments of presenilin-1 are closely related to cytoskeletal abnormalities in Alzheimer’s brains. Biochem. Biophys. Res. Comm. 256, 512–518.

    Article  PubMed  CAS  Google Scholar 

  • Tomita T., Takikawa R., Koyama A., Morohashi Y., Takasugi N., Saido T. C., et al. (1999) C terminus of presenilin is required for overproduction of amyloidogenic Ab42 through stabilization and endoproteolysis of presenilin. J. Neurosci. 19, 10,627–10,634.

    CAS  Google Scholar 

  • Tomita T., Tokuhiro S., Hashimoto T., Aiba K., Saido T. C., Maruyama K., and Iwatsubo T. (1998) Molecular dissection of domains in mutant presenilin 2 that mediate overproduction of amyloidogenic forms of amyloid beta peptides. Inability of truncated forms of PS2 with familial Alzheimer’s disease mutation to increase secretion of Abeta42. J. Biol. Chem. 273, 21,153–21,160.

    CAS  Google Scholar 

  • Tomita T., Watabiki T., Takikawa R., Morohashi Y., Takasugi N., Kopan R., et al. (2001) The first proline of PALP motif at the C terminus of presenilins is obligatory for stabilization, complex formation and {gamma}-secretase activities of presenilins. J. Biol. Chem. 276, 33,273–33,281.

    CAS  Google Scholar 

  • van de Craen M., de Jonghe C., van den Brande I., Declercq W., van Gassen G., van Criekinge W., et al. (1999) Identification of caspases that cleave presenilin-1 and presenilin-2. Five presenilin-1 (PS1) mutations do not alter the sensitivity of PS1 to caspases. FEBS Lett. 445, 149–154.

    Article  PubMed  Google Scholar 

  • Van Gassen G., De Jonghe C., Pype S., Van Criekinge W., Julliams A., Vanderhoeven I., et al. (1999) Alzheimer’s disease associated presenilin 1 interacts with HC5 and ZETA, subunits of the catalytic 20S proteasome. Neurobiol. Dis. 6, 376–391.

    Article  PubMed  Google Scholar 

  • Weihl C. C., Ghadge G. D., Miller R. J., and Roos R. P. (1999) Processing of wild-type and mutant familial Alzheimer’s disease- associated presenilin-1 in cultured neurons. J. Neurochem. 73, 31–40.

    Article  PubMed  CAS  Google Scholar 

  • Wolfe M. S., Xia W., Ostaszewski B. L., Diehl T. S., Kimberly W. T., and Selkoe D. J. (1999) Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity. Nature 398, 513–517.

    Article  PubMed  CAS  Google Scholar 

  • Xu X., Shi Y., Wu X., Gambetti P., Sui D., and Cui M. Z. (1999) Identification of a novel PSD-95/Dlg/ZO-1 (PDZ)-like protein interacting with the C terminus of presenilin-1. J. Biol. Chem. 274, 32,543–32,546.

    CAS  Google Scholar 

  • Yu G., Chen F., Levesque G., Nishimura M., Zhang D. M., Levesque L., et al. (1998) The Presenilin 1 protein is a component of a high molecular weight intracellular complex that contains beta-catenin. J. Biol. Chem. 273, 16,470–16,475.

    CAS  Google Scholar 

  • Yu G., Chen F., Nishimura M., Steiner H., Tandon A., Kawarai T., et al. (2000) Mutation of conserved aspartates affects maturation of both aspartate mutant and endogenous presenilin 1 and presenilin 2 complexes. J. Biol. Chem. 275, 27,348–27,353.

    CAS  Google Scholar 

  • Yu G., Nishimura M., Arawaka S., Levitan D., Zhang L., Tandon A., et al. (2000) Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and beta APP processing. Nature 407, 48–54.

    Article  PubMed  CAS  Google Scholar 

  • Zhang D. M., Levitan D., Yu G., Nishimura M., Chen F., Tandon A., et al. (2000) Mutation of the conserved N-terminal cysteine (Cys92) of human presenilin 1 causes increased Abeta42 secretion in mammalian cells but impaired Notch/lin-12 signalling in C. elegans. Neuroreport 11, 3227–3230.

    Article  PubMed  CAS  Google Scholar 

  • Zhang J., Kang D. E., Xia W., Okochi M., Mori H., Selkoe D. J., and Koo E. H. (1998) Subcellular distribution and turnover of presenilins in transfected cells. J. Biol. Chem. 273, 12,436–12,442.

    CAS  Google Scholar 

  • Zhou J., Liyanage U., Medina M., Ho C., Simmons A. D., Lovett M., and Kosik K. S. (1997) Presenilin 1 interaction in the brain with a novel member of the Armadillo family. Neuroreport 8, 2085–2090.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Gopal Thinakaran.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Thinakaran, G. Metabolism of Presenilins. J Mol Neurosci 17, 183–192 (2001). https://doi.org/10.1385/JMN:17:2:183

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1385/JMN:17:2:183

Index Entries

Navigation