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Presenilins

Structural aspects and posttranslational events

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Abstract

Most of early-onset forms of Alzheimer’s disease (AD) are caused by inherited mutations located on chromosomes 14 and 1, the gene products of which have been recently identified and referred to as presenilins 1 (PS1) and 2 (PS2), respectively. The first phenotypic alterations trigered by mutated PS were reported to be an increased production of the amyloid peptide (Aβ) and, more precisely, its 42 amino-acids long counterpart Aβ42. This overproduction is thought to be responsible for the genesis of the senile plaques that invade the cortical and subcortical areas of these AD-affected brains. The discovery of PSs has triggered numerous studies aimed at better understanding their normal physiology and the dysfunctions brought by the mutations that could explain, at least in part, the neurodegenerative process taking place in this syndrome. In this review, I will focus on the structural aspects of PS and on the various posttranscriptional events they undergo. I will also briefly discuss that current hypotheses concerning their normal functions and the influence of FAD-linked mutations.

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References

  1. Tanzi R. E., St. George-Hyslop P., and Gusella J. F. (1991) Molecular genetics of Alzheimer disease amyloid.J. Biol. Chem. 266, 20579–20582.

    PubMed  CAS  Google Scholar 

  2. Tanzi R. E., Kovacs D. M., Kim T-W., Moir R. D., Guenette S. Y., and Wasco W. (1996) The gene defects responsible for familial Alzheimer's disease.Neurobiol. Disease 3, 159–168.

    Article  CAS  Google Scholar 

  3. Mullan M and Crawford F. (1993) Genetic and molecular advances in Alzheimer's disease.Trends Neurosci. 16, 398–403.

    Article  PubMed  CAS  Google Scholar 

  4. Schellenberg G. D. (1995) Genetic dissection of Alzheimer disease, a heterogeneous disorder.Proc. Natl. Acad. Sci. USA 92, 8552–8559.

    Article  PubMed  CAS  Google Scholar 

  5. Kang J., Lemaire H-G., Unterbeck A., Salbaum J. M., Masters C. L., Grzeschik K-H., Multhaup G, Beyreuther K., and Müller-Hill B. (1987) The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor.Nature 325, 733–736.

    Article  PubMed  CAS  Google Scholar 

  6. Tanzi R. E., Gusella J. F., Watkins P. C., Bruns G. A. P., St. George-Hyslop P., Van Keuren M. L., Patterson D., Pagan S., Kurnit D. M., Neve R. L. (1987) Amyloid β protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus.Science 235, 880–884.

    Article  PubMed  CAS  Google Scholar 

  7. Goldgaber D., Lerman M. I., McBride O. W., Saffiotti U., and Gajdusek D. C. (1987) Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer's disease.Science 235, 887–880.

    Article  Google Scholar 

  8. Sherrington R., Rogaev E. I., Liang Y., Rogaeva E. A., Levesque G., Ikeda M., Chi H., Lin C., Li G., Holman K., Tsuda T., Mar L., Foncin J. F., Bruni A. C., Montesi M. P., Sorbi S., Rainero I., Pinessi L., Nee L., Chumakov I., Pollen D., Brookes A., Sanseau P., Polinski R. J., Wasco W., Da Silva HAR, Haines J. L., Pericak-Vance M. A., Tanzi R. E., Roses A. D., Fraser P. E., Rommens J. M., and St George-Hyslop P. H. (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease.Nature 375, 754–760.

    Article  PubMed  CAS  Google Scholar 

  9. Levy-Lahad E., Wasco W., Poorkaj P., Romano D. M., Oshima J., Pettingell W. H., Yu C., Jondro P. D., Schmidt S. D., Wang K., Crowley A. C., Fu Y. H., Guenette S. Y., Galas D., Nemens E., Wisjman E. M., Bird T. D., Schellenberg G. D., and Tanzi R. (1995) Candidate gene for the chromosome 1 familial Alzheimer's disease locus.Science 269, 973–977.

    Article  PubMed  CAS  Google Scholar 

  10. Rogaev E. I., Sherrington R., Rogaeva E. A., Levesque G., Ikeda M., Liang Y., Chi H., Lin C., Holman K., Tsuda T., Mar L., Sorbi S., Nacmias B., Piacentini S., Amaducci L., Chumakov I., Cohen D., Lannfelt L., Fraser P. E., Rommens J. M., and St Georges-Hyslop P. H. (1995) Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene.Nature 376, 775–778.

    Article  PubMed  CAS  Google Scholar 

  11. Alzheimer's Disease Collaborative Group (1996) The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset A. D. families.Nature Genet. 11, 219–222.

    Google Scholar 

  12. Mitsuda N., Roses A. D., and Vitek M. P. (1997) Transcriptional regulation of the mouse presenilin-1 gene.J. Biol. Chem. 272, 23,489–23,497.

    Article  CAS  Google Scholar 

  13. Nishiyama K., Murayama S., Suzuki T., Mitsui Y., Sakaki Y., and Kanazawa I. (1996) Presenilin 1 mRNA expression in hippocampi of sporadic Alzheimer's disease patients.Neurosci. Res. 26, 75–78.

    PubMed  CAS  Google Scholar 

  14. Tanimukai H., Sato K., Kudo T., Kashiwagi Y., Tohyama M., and Takeda M. (1999) Regional distribution of presenilin-1 messenger RNA in the embryonic rat brain: comparison with β-amyloid precursor protein messenger RNA localization.Neuroscience 90, 27–39.

    Article  PubMed  CAS  Google Scholar 

  15. Hardy J. (1997) Amyloid, the presenilins and Alzheimer's disease.Trends Neurosci. 20, 154–159.

    Article  PubMed  CAS  Google Scholar 

  16. Campion D., Brice A., Dumanchin C., Puel M., Baulac M., De La Sayette V., Hannequin D., Duyckaerts C., Michon A., Martin C., Moreau V., Penet C., Martinez M., Clerget-Darpoux F., Agid Y., and Frebourg T. (1996) A novel presenilin 1 mutation resulting in familial Alzheimer's disease with an onset age of 29 years.Neuroreport 7, 1582–1584.

    Article  PubMed  CAS  Google Scholar 

  17. Wisniewski T., Dowjat W. K., Buxbaum J. D., Khorkova O., Efthimiopoulos S., Kulczycki J., Lojkowska W., Wegiel J., Wisniewski H. M., and Frangione B. (1998) A novel polish presenilin-1 mutation (P117L) is associated with Alzheimer's disease and leads to death as early as the age of 28 years.NeuroReport 9, 217–221.

    Article  PubMed  CAS  Google Scholar 

  18. Perez-Tur J., Froelich S., Prihar G., Crook R., Baker M., Duff K., Wragg M., Busfield F., Lendon C., Clark R. F., Roques P., Fuldner R. A., Johnston J., Cowburn R., Forsell C., Axelman K., Lilius L., Houlden H., Karran E., Roberts G. W., Rossor M., Adams M. D., Hardy J., Goate A., Lannfelt L., and Hutton M. (1995) A mutation in Alzheimer's disease destroying a splice acceptor site in the presenilin-1 gene.NeuroReport 7, 297–301.

    PubMed  CAS  Google Scholar 

  19. Levy-Lahad E., Poorkaj P., Wang K., Fu Y. H., Oshima J., Mulligan J., and Schellenberg G. D. (1996) Genomic structure and expression of STM2, the chromosome 1 familial Alzheimer disease gene.Genomics 34, 198–204.

    Article  PubMed  CAS  Google Scholar 

  20. Prihar G., Fuldner R. A., Perez-Tur J., Lincoln S., Duff K., Crook R., Hardy J., Philips C. A., Venter C., Talbot C., Clark R. F., Goate A., Li J., Potter H., Karran E., Roberts G. W., Hutton M., and Adams M. D. (1996) Structure and alternative splicing of the presenilin-2 gene.NeuroReport 7, 1680–1684.

    Article  PubMed  CAS  Google Scholar 

  21. Levy-Lahad E., Wijsman E. M., Nemens E., Anderson L., Goddard A. B., Weber J. L., Bird T. D., and Schellenberg G. D. (1995) A familial Alzheimer's disease locus on chromosome 1.Science 269, 970–973.

    Article  PubMed  CAS  Google Scholar 

  22. Sherrington R., Froelich S., Sorbi S., Campion D., Chi H., Rogaeva E. A., Levesque G., Rogaev E. I., Lin C., Liang Y., Ikeda M., Mar L., Brice A., Agid Y., Percy M. E., Clerget-Darpoux F., Piacentini S., Marcon G., Nacmias B., Amaducci L., Frebourg T., Lannfelt L., Rommens J. M., and St George-Hyslop P. (1996) Alzheimer's disease associated with mutations in presenilin 2 is rare and variably penetrant.Hum. Mol. Genet. 5, 985–988.

    Article  PubMed  CAS  Google Scholar 

  23. Doan A., Thinakaran G., Borchelt D. R., Slunt H. H., Ratovitsky T., Podlisny M., Selkoe D. J., Seeger M., Gandy S. E., Price D. L., and Sisodia S. S. (1996) Protein topology of presenilin 1.Neuron 17, 1023–1030.

    Article  PubMed  CAS  Google Scholar 

  24. Lehmann S., Chiesa R., and Harris D. A. (1997) Evidence for a six-transmembrane domain structure of presenilin 1.J. Biol. Chem. 272, 12,047–12,051.

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  26. De Strooper B., Beullens M., Contreras B., Levesque L., Craessaerts K., Cordell B., Moechars D., Bollen M., Fraser P., St. George-Hyslop P., and Van Leuven F. (1997) Phosphorylation, subcellular localization, and membrane orientation of the Alzheimer's disease-associated presenilins.J. Biol. Chem. 272, 3590–3598.

    Article  PubMed  Google Scholar 

  27. Dewji N. N. and Singer S. J. (1997) The seventransmembrane spanning topography of the Alzheimer disease-related presenilin proteins in the plasma membranes of cultured cells.Proc. Natl. Acad. Sci. USA 94, 14,025–14,030.

    CAS  Google Scholar 

  28. Elder G. A., Tezapsidis N., Carter J., Shioi J., Bouras C., Li H-C., Johnston J. M., Efthimiopoulos S., Friedrich V. L., and Robakis N. K. (1996) Identification and neuron specific expression of the S182/presenilin 1 protein in human and rodent brains.J. Neurosci. Res. 45, 308–320.

    Article  PubMed  CAS  Google Scholar 

  29. Moussaoui S., Czech C., Pradier L., Blanchard V., Bonici B., Gohin M., Imperato A., and Revah F. (1996) Immunohistochemical analysis of presenilin-1 expression in the mouse brain.FEBS Letts. 383, 219–222.

    Article  CAS  Google Scholar 

  30. Kim K. S., Wegiel J., Sapienza V., Chen J., Hong H., and Wisniewski H. M. (1997) Immunoreactivity of presenilin-1 in human, rat and mouse brain.Brain Res. 757, 159–163.

    Article  PubMed  CAS  Google Scholar 

  31. Huynh D. P., Vinters H. V., Ho D. H. D., Ho V. V., and Pulst S-M. (1997) Neuronal expression and intracellular localization of presenilins in normal and Alzheimer's disease.J. Neuropathol. Exp. Neurol. 56, 1009–1017.

    Article  PubMed  CAS  Google Scholar 

  32. Culvenor J. G., Maher F., Evin G., Malchiodi-Albedi F., Cappai R., Underwood J. R., Davis J. B., Karran E. H., Roberts G. W., Beyreuther K., and Masters C. L. (1997) Alzheimer's disease-associated presenilin 1 in neuronal cells: evidence for localization to the endoplasmic reticulum-golgi intermediate compartment.J. Neurosci. Res. 49, 719–731.

    Article  PubMed  CAS  Google Scholar 

  33. Cook D. G., Sung J. C., Golde T. E., Felsenstein K. M., Wojczyk B. S., Tanzi R. E., Trojanowski J. Q., Lee V. M-Y., and Doms R. W. (1996) Expres-sion and analysis of presenilin 1 in a human neuronal system: localization in cell bodies and dendrites.Proc. Natl. Acad. Sci. USA 93, 9223–9228.

    Article  PubMed  CAS  Google Scholar 

  34. Capell A., Saffrich R., Olivo J-C., Meyn L., Walter J., Grünberg J., Mathews P., Nixon R., Dotti C., and Haass C. (1997) Cellular expression and proteolytic processing of presenilin proteins is developmentally regulated during neuronal differentiation.J. Neurochem. 69, 2432–2440.

    PubMed  CAS  Google Scholar 

  35. Busciglio J., Hartmann H., Lorenzo A., Wong C., Baumann K., Sommer B., Staufenbiel M., and Yankner B. A. (1997) Neuronal localization of presenilin-1 and association with amyloid plaques and neurofibrillary tangles in Alzheimer's disease.J. Neurosci. 17, 5101–5107.

    PubMed  CAS  Google Scholar 

  36. Kovacs D. M., Fausett H. J., K. J. P., Kim T. W., Moir R. D., Merriam D. E., Hollister R. D., Hallmark O. G., Mancini R., Felsenstein K. M., Hyman B. T., Tanzi R. E., and Wasco W. (1996) Alzheimer-associated presenilins 1 and 2: neuronal expression in brain and localization to intracellular membranes in mammalian cells.Nature. Med. 2, 224–229.

    Article  PubMed  CAS  Google Scholar 

  37. Blanchard V., Czech C., Bonici B., Clavel N., Gohin M., Dalet K., Revah F., Pradier L., Imperato A., and Moussaoui S. (1997) Immunohistochemical analysis of presenilin 2 expression in the mouse brain: distribution pattern and colocalization with presenilin 1 protein.Brain Res. 758, 209–217.

    Article  PubMed  CAS  Google Scholar 

  38. Takashima A., Sato M., Mercken M., Tanaka S., Honda T., Sato K., Murayama M., Noguchi K., Nakazato Y., and Takahashi H. (1996) Localization of Alzheimer-associated presenilin 1 in transfected COS-7 cells.Biochem. Biophys. Res. Commun. 227, 423–426.

    Article  PubMed  CAS  Google Scholar 

  39. Walter J., Capell A., Grünberg J., Pesold B., Schindzielorz A., Prior R., Podlisny M. B., Fraser P., St. George Hyslop P., Selkoe D. J., and Haass C. (1996) The Alzheimer's disease-associated presenilins are differentially phosphorylated proteins located predominantly within the endoplasmic reticulum.Mol. Med. 2, 673–691.

    PubMed  CAS  Google Scholar 

  40. Dewji N. N. and Singer S. J. (1997) Cell surface expression of the Alzheimer disease-related presenilin proteins.Proc. Natl. Acad. Sci. USA 94, 9926–9931.

    Article  PubMed  CAS  Google Scholar 

  41. Dewji N. N. and Singer S. J. (1998) Specific intercellular binding of the β-amyloid precursor protein to the presenilins induces intercellular signalling: its significance for Alzheimer's disease.Proc. Natl. Acad. Sci. USA 93, 15,055–15,060.

    Google Scholar 

  42. Li J., Xu M., Zhou H., and Ma J., Potter H. (1997) Alzheimer presenilins in the nuclear membrane, interphase kinetochores, and centrosomes suggest a role in chromosome seggregation.Cell 90, 917–927.

    Article  PubMed  CAS  Google Scholar 

  43. Walter J., Schindzielorz A., Grünberg J., and Haass C. (1999) Phosphorylation of presenilin-2 regulates its cleavage by caspases and retards progression of apoptosis.Proc. Natl. Acad. Sci. USA 96, 1391–1396.

    Article  PubMed  CAS  Google Scholar 

  44. Ward R. V., Davis J. B., Gray C. W., Barton A. J. L., Bresciani L. G., Caivano M., Murphy V. F., Duff K., Hutton M., Hardy J., Roberts G. W., and Karran E. H. (1996) Presenilin-1 is processed into two major cleavage products in neuronal cell lines.Neurodegeneration 5, 293–298.

    Article  PubMed  CAS  Google Scholar 

  45. Thinakaran G., Borchelt D. R., Lee M. K., Slunt H. H., Spitzer L., Kim G., Ratovitsky T., Davenport F., Nordstedt C., Seeger M., Hardy J., Levey A. I., Gandy S. E., Jenkins N. A., Copeland N. G., Price D. L., and Sisodia S. (1996) Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo.Neuron 17, 181–190.

    Article  PubMed  CAS  Google Scholar 

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

    CAS  Google Scholar 

  47. Baumann K., Paganetti P. A., Sturchler-Pierrat C., Wong C., Hartmann H., Cescato R., Frey P., Yankner B. A., Sommer B., and Staufenbiel M. (1997) Distinct processing of endogenous and overexpressed recombinant presenilin 1.Neurobiol. Aging 18, 181–189.

    Article  PubMed  CAS  Google Scholar 

  48. 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. Commun. 240, 728–731.

    Article  PubMed  CAS  Google Scholar 

  49. Capell A., Grünberg J., Pesold B., Diehlmann A., Citron M., Nixon R., Beyreuther K., Selkoe D. J., and Haass C. (1998) The proteolytic fragments of the Alzheimer's disease-associated presenilin-1 form heterodimers and occur as a 100–150-kDa molecular mass.J. Biol. Chem. 273, 3205–3211.

    Article  PubMed  CAS  Google Scholar 

  50. 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 

  51. Okochi M, Ishii K., Usami M., Sahara N., Kametani F., Tanaka K., Frazer P. E., Ikeda M., Saunders A. M., Hendriks L., Shoji S-I., Nee L. E., Martin J-J., Van Broeckhoven C., St. George-Hyslop P., Roses A. D., and Mori H. (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 

  52. Hendriks L., Thinakaran G., Harris C. L., De Jonghe C., Martin J. J., Sisodia S. S., and Van Broeckoven 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 

  53. Murayama O., Honda T., Mercken M., Murayama M., Yasutake K., Nihonmatsu N., Nakazato Y., Michel G., Song S., Sato K., Takahashi H., and Takashima A. (1997) Different effects of Alzheimer-associated mutations of presenilin 1 on its processing.Neurosci. Lett. 229, 61–64.

    Article  PubMed  CAS  Google Scholar 

  54. Mercken M., Takahashi H., Honda T., Sato K., Murayama M., Nakazato Y., Noguchi K., Imahori K., and Takashima A. (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 

  55. Lee M. K., Borchelt D. R., Kim G., Thinakaran G., Slunt H. H., Ratovitski T., Martin L. J., Kittur A., Gandy S., Levey A. I., Jenkins N., Copeland N., Price D. L., and Sisodia S. S. (1997) Hyperaccumulation of FAD-linked presenilin 1 variants in vivo.Nature Med. 3, 756–760.

    Article  PubMed  CAS  Google Scholar 

  56. Seeger M., Nordstedt C., Petanceska S., Kovacs D. M., Gouras G. K., Hahne S., Fraser P., Levesque L., Czernik A. J., St-George-Hyslop P., Sisodia S. S., Thinakaran G., Tanzi R. E., Greengard P., and Gandy S. (1997) Evidence for phosphorylation and oligomeric assembly of presenilin 1.Proc. Natl. Acad. Sci. USA 94, 5090–5094.

    Article  PubMed  CAS  Google Scholar 

  57. Walter J., Grünberg J., Capell A., Pesold B., Schindzielorz A., Citron M., Mendla K., StGeorge-Hyslop P., Multhaup G., Selkoe D. J., and Haass C. (1997) Proteolytic processing of the Alzheimer disease associated presenilin-1 generates an in vivo substrate for protein kinase C.Proc. Natl. Acad. Sci. USA 94, 5349–5354.

    Article  PubMed  CAS  Google Scholar 

  58. Loetscher H., Deuschle U., Brockhaus M., Reinhard D., Nelboeck P., Mous J., Grünberg J., Haass C., and Jacobsen H. (1997) Presenilins are processed by caspase-like proteases.J. Biol. Chem. 272, 20,655–20,659.

    Article  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  60. Grünberg 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  Google Scholar 

  61. van de Craen M., de Jonghe C., van den Brande I., Declercq W., van Gassen G., van Criekinge W., Vanderhoeven I., Fiers W., van Broeckhoven C., Hendricks L., and Vandenabeele P. (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.Neurosci. Lett. 260, 149–154.

    Article  Google Scholar 

  62. Dewji N. N., Do C., and Singer S. J. (1997) On the spurious endoproteolytic processing of the presenilin proteins in cultured cells and tissues.Proc. Natl. Acad. Sci. USA 94, 14,031–14,036.

    CAS  Google Scholar 

  63. Marambaud P., Ancolio K., Lopez-Perez E., and Checler F. (1998) Proteasome inhibitors prevent the degradation of familial Alzheimer's disease-linked presenilin 1 and trigger increased Aβ42 secretion by human cells.Mol. Med. 4, 146–156.

    Google Scholar 

  64. Honda T., Yasutake K., Nihonmatsu N., Mercken M., Takahashi H., Murayama O., Sato K., Omori A., Tsubuki S., Saido T. C., and Takashima A. (1999) Dual roles of proteasome in the metabolism of presenilin 1.J. Neurochem. 72, 255–261.

    Article  PubMed  CAS  Google Scholar 

  65. Steiner H., Capell A., Pesold B., Citron M., Kloetzel P. M., Selkoe D. J., Romig H., Mendla K., and Haass C. (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 

  66. Fraser P. E., Levesque G., Yu G., Mills L. R., Thirwell J., Frantseva M., Gandy S. E., Seeger M., Carlen P. L., and St. George-Hyslop P. (1998) Presenilin 1 is actively degraded by the 26S proteasome.Neurobiol. Aging 19, S19-S21.

    Article  PubMed  CAS  Google Scholar 

  67. Marambaud P., Alves da Costa C., Ancolio K., and Checler F. (1998) Alzheimer's disease-linked mutation of presenilin 2 (N141I-PS2) drastically lowers APPα secretion: control by the proteasome.Biochem. Biophys. Res. Commun. 252, 134–138.

    Article  PubMed  CAS  Google Scholar 

  68. Alves da Costa C., Ancolio K., and Checler F. (1999) C-terminal maturation fragments of presenilin 1 and 2 control secretion of APPα and Aβ by human cells and are degraded by the proteasome.Mol. Med. 5, 160–168.

    CAS  Google Scholar 

  69. Levitan D. and Greenwald I. (1995) Facilitation oflin-12-mediated signalling bysel-12, aCaenorhabditis elegans S182 Alzheimer's disease geneNature 377, 351–354.

    Article  PubMed  CAS  Google Scholar 

  70. Levitan D., Doyle T. G., Brousseau D., Lee M. K., Thinakaran G., Slunt H. H., Sisodia S. S., and Greenwald I. (1996) Assessment of normal and mutant human presenilin function inCaenorhabditis elegans.Proc. Natl. Acad. Sci. USA 93, 14,940–14,944.

    Article  CAS  Google Scholar 

  71. Ray W. J., Yao M., Nowotny P., Mumm J., Zhang W., Wu J., Kopan R., and Goate A. (1999) Evidence for a physical interaction between presenilin and Notch.Proc. Natl. Acad. Sci. USA 96, 3263–3268.

    Article  PubMed  CAS  Google Scholar 

  72. De strooper B., Annaert W., Cupers P., Saftig P., Craessaerts K., Mumm J. S., Schroeter E. H., Schrijvers V., Wolfe M. S., Ray W. J., Goate A., and Kopan R. (1999) A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain.Nature 398, 518–522.

    Article  PubMed  CAS  Google Scholar 

  73. Ye Y., Lukinova N., and Fortini M. E. (1999) Neurogenic phenotypes and altered Notch processing in drosophila presenilin mutants.Nature 398, 525–529.

    Article  PubMed  CAS  Google Scholar 

  74. Struhl G. and Greenwald I. (1999) Presenilin is required for activity and nuclear access of Notch in drosophila.Nature 398, 522–525.

    Article  PubMed  CAS  Google Scholar 

  75. De Strooper B., Saftig P., Craessaerts K., Vanderstichele H., Guhde G., Von Figura K., and Van Leuven F. (1998) Deficiency of presenilin 1 inhibits the normal cleavage of amyloid precursor protein.Nature 391, 387–390.

    Article  PubMed  CAS  Google Scholar 

  76. 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 

  77. Naruse S., Thinakaran G., Luo J-J., Kusiak J. W. T. T., Iwatsubo T., Qian X., Ginty D. D., Price D. L., Borchelt D. R., Wong P. C., and Sisodia S. S. (1998) Effects of PS1 deficiency on membrane protein trafficking in neurons.Neuron 21, 1213–1221.

    Article  PubMed  CAS  Google Scholar 

  78. Nishimura M., Yu G., Levesque G., Zhang D. M., Ruel L., Chen F., Milman P., Holmes E., Liang Y., Kawarai T., Jo E., Supala A., Rogaeva E., Xu D-M., Janus C., Levesque L., Bi Q., Duthie M., Rozmahel R., Mattila K., Lannfelt L., Westaway D., Mount H. T. J., Woodgett J., Fraser P. E., and St George-Hyslop P. (1999) Presenilin mutations associated with Alzheimer's disease cause defective intracellular trafficking of β-catenin, a component of the presenilin protein complex.Nature Med. 5, 164–169.

    Article  PubMed  CAS  Google Scholar 

  79. Yu G., Chen F., Levesque G., Nishimura M., Zhang D-M., Levesque L., Rogaeva E., Xu D., Liang Y., Duthie M., St George-Hyslop P. H., and Fraser P. E. (1998) The presenilin 1 protein is component of a high molecular weight intracellular complex that contains β-catenin.J. Biol. Chem. 273, 16,470–16,475.

    CAS  Google Scholar 

  80. Tesco G., Kim T-W., Dielhmann A., Beyreuther K., and Tanzi R. (1998) Abrogation of the presenilin 1/β-catenin interaction and preservation of the heterodimeric presenilin 1 complex following caspase activation.J. Biol. Chem. 273, 33,909–33,914.

    Article  CAS  Google Scholar 

  81. Zhang Z., Hartmann H., Do V. M., Abramowski D., Sturchler-Pierrat C., Staufenbiel M., Sommer B., van de wetering M., Clevers H., Saftig P., De Strooper B., He X., and Yankner B. A. (1998) Destabilization of β-catenin by mutations in presenilin-1potentiates neuronal apoptosis.Nature 395, 698–702.

    Article  PubMed  CAS  Google Scholar 

  82. Levesque G., Yu G., Nishimura M., Zhang D. M., Levesque L., Yu H., Xu D., Liang Y., Rogaeve E., Ikeda M., Duthie M., Murgolo N., Wang L., Vander Vere P., Bayne M. L., Strader C. D., Rommens J. M., Fraser P. E., and St. George-Hyslop P. (1999) Presenilins interact with armadillo proteins including neural-specific plakophilin-related protein and β-catenin.J. Neurochem. 72, 999–1008.

    Article  PubMed  CAS  Google Scholar 

  83. Haass C. (1997) Presenilins, genes for life and death.Neurons 18, 687–690.

    Article  CAS  Google Scholar 

  84. Hutton M. and Hardy J. (1997) The presenilins and Alzheimer's disease.Human Mol. Genet. 6, 1639–1646.

    Article  CAS  Google Scholar 

  85. Mattson M. P., Gue Q., Furukawa K., and Pedersen W. A. (1998) Presenilins, the endoplasmic reticulum, and neuronal apoptosis in Alzheimer's disease.J. Neurochem. 70, 1–14.

    Article  PubMed  CAS  Google Scholar 

  86. Checler F. (1999) Presenilins: multifunctional proteins involved in Alzheimer's disease Pathology.LIFE, in press.

  87. Smine A., Xu X., Nishiyama K., Katada T., Gambetti P., Yadav S. P., Wu X., Shi Y-C., Yasuhara S., Homburger V., and Okamoto T. (1998) Regulation of brain G-protein Go by Alzheimer's disease gene presenilin-1.J. Biol. Chem. 273, 16,281–16,288.

    Article  CAS  Google Scholar 

  88. Dumanchin C., Czech C., Campion D., Cuif M-H., Poyot T., Charbonnier F., Goud B., Pradier L., and Frebourg T. (1999) Presenilins interact with Rab11, a small GTPase involved in the regulation of vesicular transport.Hum. Mol. Genet. 8, 1263–1269.

    Article  PubMed  CAS  Google Scholar 

  89. Buxbaum J. D., Choi E-K., Luo Y., Lilliehook C., Crowley A. C., Merriam D. E., and Wasco W. (1998) Calsenilin: A calcium-binding protein that interacts with the presenilins and regulates the level of a presenilin fragment.Nature Med. 4, 1177–1181.

    Article  PubMed  CAS  Google Scholar 

  90. Takashima A., Murayama M., Murayama O., Kohno T., Honda T., Yasutake K., Nihonmatsu N., Mercken M., Yamaguchi H., Sugihara S., and Wolozin B. (1998) Presenilin1 associates with glycogen synthase kinase-3β and its substrate tau.Proc. Natl. Acad. Sci. USA 95, 9637–9641.

    Article  PubMed  CAS  Google Scholar 

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  1. Institut de Pharmacologie Moléculaire et Cellulaire, UPR 411 du CNRS, 660 route des Lucioles, Sophia Antipolis, 06560, Valbonne, France

    Frédéric Checler

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Checler, F. Presenilins. Mol Neurobiol 19, 255–265 (1999). https://doi.org/10.1007/BF02821716

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