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Gene Review

Psn  -  Presenilin

Drosophila melanogaster

Synonyms: CG18803, CG5868, DPS, DPsn, DmPS, ...
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Psychiatry related information on Psn

  • To assess the potential of Drosophila to analyze clinically graded aspects of human disease, we developed a transgenic fly model to characterize Presenilin (PS) gene mutations that cause early-onset familial Alzheimer's disease (FAD) [1].

High impact information on Psn

  • Furthermore, we provide evidence that presenilin is required for the proteolytic release of the intracellular domain from the membrane following activation of Notch by ligand [2].
  • Here we describe loss-of-function mutations in the Drosophila Presenilin gene that cause lethal Notch-like phenotypes such as maternal neurogenic effects during embryogenesis, loss of lateral inhibition within proneural cell clusters, and absence of wing margin formation [3].
  • Genetic analysis of familial Alzheimer's disease has revealed that mutations in the gamma-secretase enzyme presenilin promote toxic Abeta secretion; however, presenilin mutations might also influence tau hyperphosphorylation and neurodegeneration through gamma-secretase-independent mechanisms [4].
  • The transmembrane glycoprotein Nicastrin was identified in a complex with the multipass membrane protein Presenilin [5].
  • Subcomplex levels of Aph-1 are down-regulated by stepwise addition of Psn, suggesting that Aph-1 might not enter the mature complex [6].

Biological context of Psn

  • The catalytic subunit of gamma-secretase is thought to be Presenilin, which is required for both the cleavage of APP and in the processing of Notch [7].
  • The loss-of-function recessive point mutations located in the C-terminal region of Psn, that cause an early pupal-lethal phenotype resembling Notch mutant in vivo, disrupted the HMW complex formation, and abolished gamma-secretase activities in cultured cells [8].
  • Here we show that null mutations in the Drosophila Presenilin gene abolish Notch signal transduction and prevent its intracellular domain from entering the nucleus [2].
  • Here we report the identification of a Drosophila melanogaster homologue of human PS genes, Dps, which maps to band 77B-C on chromosome 3 and is expressed at multiple developmental stages [9].
  • Then, the receptor is cleaved by a proteolytic mechanism in which Presenilin plays an important role, and the intracellular domain is transferred to the nucleus, where it, together with the Suppressor of Hairless protein, constitutes a transcription factor which activates the Notch target genes, mainly located in the Enhancer of split complex [10].

Anatomical context of Psn


Physical interactions of Psn

  • Aph-1 and Nct may form a subcomplex that stabilizes the Psn holoprotein at an early step in gamma-secretase assembly [6].
  • Our data suggest that the proper assembly of the Aph-1.nicastrin subcomplex with presenilin is the prerequisite for the trafficking as well as the enzymatic activity of the gamma-secretase complex and that Aph-1 functions as a stabilizing scaffold in the assembly of this complex [12].

Regulatory relationships of Psn

  • Taken together, these results indicate that Drosophila presenilin is required for proper neuronal differentiation and may regulate the subcellular localization of Notch proteins within cells, necessary for their accumulation and subsequent signaling capabilities [13].

Other interactions of Psn

  • These results demonstrate that Aph-1 and Pen-2 are essential cofactors for Psn, but that they play different roles in gamma-secretase assembly and activation [6].
  • Coexpression of all four proteins leads to high level accumulation of mature Psn and increased proteolysis of Notch [6].
  • Aberrant gamma-secretase cleavage of APP underlies the majority of early onset, familial AD. gamma-Secretase resides in a large multi-protein complex, of which Presenilin, Nicastrin, APH-1 and PEN-2 are four essential components [14].
  • Presenilin 1 interaction in the brain with a novel member of the Armadillo family [15].
  • Therefore, we utilized the two hybrid system and confirmatory co-immunoprecipitations to identify a novel catenin, termed gamma-catenin, which interacts with PS1 and is principally expressed in brain [11].


  1. Modeling clinically heterogeneous presenilin mutations with transgenic Drosophila. Seidner, G.A., Ye, Y., Faraday, M.M., Alvord, W.G., Fortini, M.E. Curr. Biol. (2006) [Pubmed]
  2. Presenilin is required for activity and nuclear access of Notch in Drosophila. Struhl, G., Greenwald, I. Nature (1999) [Pubmed]
  3. Neurogenic phenotypes and altered Notch processing in Drosophila Presenilin mutants. Ye, Y., Lukinova, N., Fortini, M.E. Nature (1999) [Pubmed]
  4. gamma-Cleavage-Independent Functions of Presenilin, Nicastrin, and Aph-1 Regulate Cell-Junction Organization and Prevent Tau Toxicity In Vivo. Doglio, L.E., Kanwar, R., Jackson, G.R., Perez, M., Avila, J., Dingwall, C., Dotti, C.G., Fortini, M.E., Feiguin, F. Neuron (2006) [Pubmed]
  5. Nicastrin is required for Presenilin-mediated transmembrane cleavage in Drosophila. Chung, H.M., Struhl, G. Nat. Cell Biol. (2001) [Pubmed]
  6. Different cofactor activities in gamma-secretase assembly: evidence for a nicastrin-Aph-1 subcomplex. Hu, Y., Fortini, M.E. J. Cell Biol. (2003) [Pubmed]
  7. Drosophila nicastrin is essential for the intramembranous cleavage of notch. López-Schier, H., St Johnston, D. Dev. Cell (2002) [Pubmed]
  8. The mechanism of gamma-secretase activities through high molecular weight complex formation of presenilins is conserved in Drosophila melanogaster and mammals. Takasugi, N., Takahashi, Y., Morohashi, Y., Tomita, T., Iwatsubo, T. J. Biol. Chem. (2002) [Pubmed]
  9. Cloning and characterization of the Drosophila presenilin homologue. Boulianne, G.L., Livne-Bar, I., Humphreys, J.M., Liang, Y., Lin, C., Rogaev, E., St George-Hyslop, P. Neuroreport (1997) [Pubmed]
  10. General outlines of the molecular genetics of the Notch signalling pathway in Drosophila melanogaster: a review. Portin, P. Hereditas (2002) [Pubmed]
  11. Presenilin 1 interaction in the brain with a novel member of the Armadillo family. Zhou, J., Liyanage, U., Medina, M., Ho, C., Simmons, A.D., Lovett, M., Kosik, K.S. Neuroreport (1997) [Pubmed]
  12. Aph-1 contributes to the stabilization and trafficking of the gamma-secretase complex through mechanisms involving intermolecular and intramolecular interactions. Niimura, M., Isoo, N., Takasugi, N., Tsuruoka, M., Ui-Tei, K., Saigo, K., Morohashi, Y., Tomita, T., Iwatsubo, T. J. Biol. Chem. (2005) [Pubmed]
  13. Drosophila presenilin is required for neuronal differentiation and affects notch subcellular localization and signaling. Guo, Y., Livne-Bar, I., Zhou, L., Boulianne, G.L. J. Neurosci. (1999) [Pubmed]
  14. A reporter for amyloid precursor protein gamma-secretase activity in Drosophila. Guo, M., Hong, E.J., Fernandes, J., Zipursky, S.L., Hay, B.A. Hum. Mol. Genet. (2003) [Pubmed]
  15. Presenilin 1 interaction in the brain with a novel member of the Armadillo family. Zhou, J., Liyanage, U., Medina, M., Ho, C., Simmons, A.D., Lovett, M., Kosik, K.S. Neuroreport (1997) [Pubmed]
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