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PMID: 10811883 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't

Separation of presenilin function in amyloid beta-peptide generation and endoproteolysis of Notch.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 97 ·No. 11 ·2000-05-23 ·Pages 5913-8

Kulic L, Walter J, Multhaup G, Teplow DB, Baumeister R, Romig H, Capell A, Steiner H, Haass C

Abstract

Most of the genetically inherited Alzheimer's disease cases are caused by mutations in the presenilin genes, PS1 and PS2. PS mutations result in the enhanced production of the highly amyloidogenic 42/43 amino acid variant of amyloid beta-peptide (Abeta). We have introduced arbitrary mutations at position 286 of PS1, where a naturally occurring PS1 mutation has been described (L286V). Introduction of charged amino acids (L286E or L286R) resulted in an increase of Abeta42/43 production, which reached almost twice the level of the naturally occurring PS1 mutation. Although pathological Abeta production was increased, endoproteolysis of Notch and nuclear transport of its cytoplasmic domain was significantly inhibited. These results demonstrate that the biological function of PS proteins in the endoproteolysis of beta-amyloid precursor protein and Notch can be separated.

MeSH Terms
Alzheimer Disease/genetics,metabolism Amino Acid Substitution Amyloid beta-Peptides/biosynthesis Amyloid beta-Protein Precursor/metabolism Animals Animals, Genetically Modified Caenorhabditis elegans/genetics Cells, Cultured Codon/genetics Humans Membrane Proteins/chemistry,genetics,metabolism,physiology Models, Molecular Mutagenesis, Site-Directed Point Mutation Presenilin-1 Protein Processing, Post-Translational Receptors, Notch Substrate Specificity
Chemicals
Amyloid beta-Peptides Amyloid beta-Protein Precursor Codon Membrane Proteins PSEN1 protein, human Presenilin-1 Receptors, Notch
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Kulic L
Adolf-Butenandt-Institute, Department of Biochemistry, Laboratory for Alzheimer's Disease Research, Ludwig Maximilians University, 80336 Munich, Germany.
Walter J
Multhaup G
Teplow D B
Baumeister R
Romig H
Capell A
Steiner H
Haass C
References (55)
55 references, click to expand
  1. The presenilins in Alzheimer's disease--proteolysis holds the key.
    Science. 1999 Oct 29;286(5441):916-9 PMID: 10542139
  2. Familial Alzheimer's disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo.
    Neuron. 1996 Nov;17(5):1005-13 PMID: 8938131
  3. Mice lacking both presenilin genes exhibit early embryonic patterning defects.
    Genes Dev. 1999 Nov 1;13(21):2801-10 PMID: 10557208
  4. The influence of endoproteolytic processing of familial Alzheimer's disease presenilin 2 on abeta42 amyloid peptide formation.
    J Biol Chem. 1999 Dec 3;274(49):35233-9 PMID: 10575009
  5. Cell surface presenilin-1 participates in the gamma-secretase-like proteolysis of Notch.
    J Biol Chem. 1999 Dec 17;274(51):36801-7 PMID: 10593990
  6. Assessment of normal and mutant human presenilin function in Caenorhabditis elegans.
    Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14940-4 PMID: 8962160
  7. The Alzheimer's disease-associated presenilins are differentially phosphorylated proteins located predominantly within the endoplasmic reticulum.
    Mol Med. 1996 Nov;2(6):673-91 PMID: 8972483
  8. Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice.
    Nat Med. 1997 Jan;3(1):67-72 PMID: 8986743
  9. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein.
    Nature. 1998 Jan 22;391(6665):387-90 PMID: 9450754
  10. 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. 1998 Feb 6;273(6):3205-11 PMID: 9452432
  11. An Alzheimer's disease-linked PS1 variant rescues the developmental abnormalities of PS1-deficient embryos.
    Neuron. 1998 Mar;20(3):603-9 PMID: 9539132
  12. Mutant human presenilin 1 protects presenilin 1 null mouse against embryonic lethality and elevates Abeta1-42/43 expression.
    Neuron. 1998 Mar;20(3):611-7 PMID: 9539133
  13. Detection of a novel intraneuronal pool of insoluble amyloid beta protein that accumulates with time in culture.
    J Cell Biol. 1998 May 18;141(4):1031-9 PMID: 9585420
  14. Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain.
    Nature. 1998 May 28;393(6683):382-6 PMID: 9620803
  15. The presenilin 1 protein is a component of a high molecular weight intracellular complex that contains beta-catenin.
    J Biol Chem. 1998 Jun 26;273(26):16470-5 PMID: 9632714
  16. Stable association of presenilin derivatives and absence of presenilin interactions with APP.
    Neurobiol Dis. 1998 Apr;4(6):438-53 PMID: 9666482
  17. Human presenilin-1, but not familial Alzheimer's disease (FAD) mutants, facilitate Caenorhabditis elegans Notch signalling independently of proteolytic processing.
    Genes Funct. 1997 Apr;1(2):149-59 PMID: 9680315
  18. Additive effects of PS1 and APP mutations on secretion of the 42-residue amyloid beta-protein.
    Neurobiol Dis. 1998 Aug;5(2):107-16 PMID: 9746908
  19. Expression of Alzheimer's disease-associated presenilin-1 is controlled by proteolytic degradation and complex formation.
    J Biol Chem. 1998 Nov 27;273(48):32322-31 PMID: 9822712
  20. Reverse genetic analysis of Caenorhabditis elegans presenilins reveals redundant but unequal roles for sel-12 and hop-1 in Notch-pathway signaling.
    Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2497-502 PMID: 10051671
  21. The biological and pathological function of the presenilin-1 Deltaexon 9 mutation is independent of its defect to undergo proteolytic processing.
    J Biol Chem. 1999 Mar 19;274(12):7615-8 PMID: 10075646
  22. Peptidomimetic probes and molecular modeling suggest that Alzheimer's gamma-secretase is an intramembrane-cleaving aspartyl protease.
    Biochemistry. 1999 Apr 13;38(15):4720-7 PMID: 10200159
  23. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity.
    Nature. 1999 Apr 8;398(6727):513-7 PMID: 10206644
  24. A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain.
    Nature. 1999 Apr 8;398(6727):518-22 PMID: 10206645
  25. Presenilin is required for activity and nuclear access of Notch in Drosophila.
    Nature. 1999 Apr 8;398(6727):522-5 PMID: 10206646
  26. Neurogenic phenotypes and altered Notch processing in Drosophila Presenilin mutants.
    Nature. 1999 Apr 8;398(6727):525-9 PMID: 10206647
  27. Proteolytic release and nuclear translocation of Notch-1 are induced by presenilin-1 and impaired by pathogenic presenilin-1 mutations.
    Proc Natl Acad Sci U S A. 1999 Jun 8;96(12):6959-63 PMID: 10359821
  28. Mutagenesis identifies new signals for beta-amyloid precursor protein endocytosis, turnover, and the generation of secreted fragments, including Abeta42.
    J Biol Chem. 1999 Jul 2;274(27):18851-6 PMID: 10383380
  29. Translating cell biology into therapeutic advances in Alzheimer's disease.
    Nature. 1999 Jun 24;399(6738 Suppl):A23-31 PMID: 10392577
  30. Presenilins, processing of beta-amyloid precursor protein, and notch signaling.
    Neuron. 1999 Jun;23(2):201-4 PMID: 10399926
  31. Are presenilins intramembrane-cleaving proteases? Implications for the molecular mechanism of Alzheimer's disease.
    Biochemistry. 1999 Aug 31;38(35):11223-30 PMID: 10471271
  32. A loss of function mutation of presenilin-2 interferes with amyloid beta-peptide production and notch signaling.
    J Biol Chem. 1999 Oct 1;274(40):28669-73 PMID: 10497236
  33. Presenilin 2 deficiency causes a mild pulmonary phenotype and no changes in amyloid precursor protein processing but enhances the embryonic lethal phenotype of presenilin 1 deficiency.
    Proc Natl Acad Sci U S A. 1999 Oct 12;96(21):11872-7 PMID: 10518543
  34. Zebrafish (Danio rerio) presenilin promotes aberrant amyloid beta-peptide production and requires a critical aspartate residue for its function in amyloidogenesis.
    Biochemistry. 1999 Oct 12;38(41):13602-9 PMID: 10521267
  35. Presenilin 1 controls gamma-secretase processing of amyloid precursor protein in pre-golgi compartments of hippocampal neurons.
    J Cell Biol. 1999 Oct 18;147(2):277-94 PMID: 10525535
  36. Evidence for phosphorylation and oligomeric assembly of presenilin 1.
    Proc Natl Acad Sci U S A. 1997 May 13;94(10):5090-4 PMID: 9144195
  37. Proteolytic processing of the Alzheimer disease-associated presenilin-1 generates an in vivo substrate for protein kinase C.
    Proc Natl Acad Sci U S A. 1997 May 13;94(10):5349-54 PMID: 9144240
  38. Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm.
    Nature. 1997 May 15;387(6630):288-92 PMID: 9153393
  39. Skeletal and CNS defects in Presenilin-1-deficient mice.
    Cell. 1997 May 16;89(4):629-39 PMID: 9160754
  40. 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. 1997;3(4):325-37 PMID: 9173929
  41. Presenilins: genes for life and death.
    Neuron. 1997 May;18(5):687-90 PMID: 9182794
  42. Intracellular generation and accumulation of amyloid beta-peptide terminating at amino acid 42.
    J Biol Chem. 1997 Jun 27;272(26):16085-8 PMID: 9195901
  43. Evidence that levels of presenilins (PS1 and PS2) are coordinately regulated by competition for limiting cellular factors.
    J Biol Chem. 1997 Nov 7;272(45):28415-22 PMID: 9353300
  44. Lack of requirement for presenilin1 in Notch1 signaling.
    Curr Biol. 1999 Dec 16-30;9(24):1493-6 PMID: 10607593
  45. Presenilin-1 differentially facilitates endoproteolysis of the beta-amyloid precursor protein and Notch.
    Nat Cell Biol. 2000 Apr;2(4):205-11 PMID: 10783238
  46. Amyloid beta-peptide is produced by cultured cells during normal metabolism.
    Nature. 1992 Sep 24;359(6393):322-5 PMID: 1383826
  47. Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production.
    Nature. 1992 Dec 17;360(6405):672-4 PMID: 1465129
  48. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease.
    Nature. 1995 Jun 29;375(6534):754-60 PMID: 7596406
  49. Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer's disease gene.
    Nature. 1995 Sep 28;377(6547):351-4 PMID: 7566091
  50. The Swedish mutation causes early-onset Alzheimer's disease by beta-secretase cleavage within the secretory pathway.
    Nat Med. 1995 Dec;1(12):1291-6 PMID: 7489411
  51. Alzheimer-associated presenilins 1 and 2: neuronal expression in brain and localization to intracellular membranes in mammalian cells.
    Nat Med. 1996 Feb;2(2):224-9 PMID: 8574969
  52. Electrophoretic separation of betaA4 peptides (1-40) and (1-42).
    Anal Biochem. 1996 May 15;237(1):24-9 PMID: 8660532
  53. Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo.
    Neuron. 1996 Jul;17(1):181-90 PMID: 8755489
  54. Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease.
    Nat Med. 1996 Aug;2(8):864-70 PMID: 8705854
  55. Amyloidogenic function of the Alzheimer's disease-associated presenilin 1 in the absence of endoproteolysis.
    Biochemistry. 1999 Nov 2;38(44):14600-5 PMID: 10545183
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.100049897
Published
2000-05-23
Pages
5913-8
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC18533
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.100049897 PMC Full Text View journal details
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