Selkoe, Dennis J

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ROLE OF PRESENILIN IN NOTCH AND APP MATURATION

Goate, Alison M

30 September 1999 - 31 July 2005
NATIONAL INSTITUTE ON AGING
Total Funding: $ 1,341,635

(From Abstract) Molecular genetic studies of familial Alzheimer's disease (FAD) have led to the identification of three genes which, when mutated can cause Alzheimer's disease (AD); beta-amyloid precursor protein (APP) and two related genes presenilin 1 (PS1) and presenilin 2 (PS2). The normal function of each of these molecules remains unknown, however, FAD mutations in all three genes result in an increase in levels of Ab42, an amyloidogenic fragment derived from APP by proteolytic processing. The dominant inheritance of the FAD phenotype suggests that these mutations either cause a gain of function or a loss of function via a dominant negative mechanism. PS1 knock-out mice are not viable and show multiple developmental abnormalities. Neurons derived from PS1 knock-out mice show a decrease in Ab levels suggesting that PS1 is required for normal APP processing and that the FAD mutations are not loss of function alleles. Genetic experiments have demonstrated that two presenilin homologs exist in C. elegans: sel-12 and hop-1, and that these molecules undergo similar endoproteolytic processing to their mammalian counterparts. Mutations that reduce sel-12 activity or sel-12 and hop-1 activity cause phenotypes that are consistent with a reduction in signaling through the lin-12 and glp-12 (Notch homologs) pathways. The phenotype of constitutively active lin-12 mutants lacking the extracellular and transmembrane domains are not modified by reduction of sel-12 activity suggesting that the sel-12 affects Notch signaling upstream of Notch activation. PS are membrane proteins with multiple membrane spanning domains that are primarily located within the endoplasmic reticulum. To determine the normal function of PS1 we will examine Notch maturation and processing in the presence and absence of functional PS1. We will extend our observations to the effect of PS function on APP maturation and processing and finally we will examine the effect of FAD mutations on the normal function of PS1 with respect to both Notch and APP. Specifically, we hypothesize that loss of PS function leads to reduced Notch signaling and reduced Ab because PS is required for normal Notch and APP maturation within the secretory pathway. We also hypothesize that FAD-causing mutations modify the normal activity of PS1 and that this change will have no effect on Notch signaling but will subtly alter APP processing. Through these studies we hope to determine the normal function of PS1 and to gain a better understanding of the role of PS1 in AD pathogenesis. We also anticipate that these studies will increase our understanding of the Notch signaling, a process that is important not only for many developmental decisions but for cancer as well.

9 Resulting Publications

• 1.

  2006

  Emily S Walker; Maribel Martinez; Jun Wang; Alison Goate

  Conserved residues in juxtamembrane region of the extracellular domain of nicastrin are essential for gamma-secretase complex formation.

  Journal of neurochemistry 2006;98(1):300-9.

• 2.

  2006

  Jun Wang; Dirk Beher; Andrew C Nyborg; Mark S Shearman; Todd E Golde; Alison Goate

  C-terminal PAL motif of presenilin and presenilin homologues required for normal active site conformation.

  Journal of neurochemistry 2006;96(1):218-27.

• 3.

  2005

  A L Brunkan; M Martinez; J Wang; E S Walker; D Beher; M S Shearman; A M Goate

  Two domains within the first putative transmembrane domain of presenilin 1 differentially influence presenilinase and gamma-secretase activity.

  Journal of neurochemistry 2005;94(5):1315-28.

• 4.

  2005

  Anne L Brunkan; Maribel Martinez; Emily S Walker; Alison M Goate

  Presenilin endoproteolysis is an intramolecular cleavage.

  Molecular and cellular neurosciences 2005;29(1):65-73.

• 5.

  2005

  A L Brunkan; M Martinez; J Wang; E S Walker; A M Goate

  A domain at the C-terminus of PS1 is required for presenilinase and gamma-secretase activities.

  Journal of neurochemistry 2005;92(5):1158-69.

• 6.

  2005

  Emily S Walker; Maribel Martinez; Anne L Brunkan; Alison Goate

  Presenilin 2 familial Alzheimer's disease mutations result in partial loss of function and dramatic changes in Abeta 42/40 ratios.

  Journal of neurochemistry 2005;92(2):294-301.

• 7.

  2004

  Silva Hecimovic; Jun Wang; Georgia Dolios; Maribel Martinez; Rong Wang; Alison M Goate

  Mutations in APP have independent effects on Abeta and CTFgamma generation.

  Neurobiology of disease 2004;17(2):205-18.

• 8.

  2003

  Eric H Schroeter; Ma Xenia G Ilagan; Anne L Brunkan; Silva Hecimovic; Yue-ming Li; Min Xu; Huw D Lewis; Meera T Saxena; Bart De Strooper; Archie Coonrod; et al.

  A presenilin dimer at the core of the gamma-secretase enzyme: insights from parallel analysis of Notch 1 and APP proteolysis.

  Proceedings of the National Academy of Sciences of the United States of America 2003;100(22):13075-80.

• 9.

  2000

  R Kopan; A Goate

  A common enzyme connects notch signaling and Alzheimer's disease.

  Genes & development 2000;14(22):2799-806.

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