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Francis R, McGrath G, Zhang J, Ruddy DA, Sym M, Apfeld J, Nicoll M, Maxwell M, Hai B, Ellis MC, Parks AL, Xu W, Li J, Gurney M, Myers RL, Himes CS, Hiebsch R, Ruble C, Nye JS, Curtis D.
aph-1 and pen-2 are required for Notch pathway signaling, gamma-secretase cleavage of betaAPP, and presenilin protein accumulation. Dev Cell.
2002 Jul;3(1):85-97.
PubMed Abstract, View on AlzSWAN
Corresponding Author: Daniel Curtis
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Comments on Paper and Primary News |
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Comment by: John Portovski
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Submitted 4 March 2006
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Posted 5 March 2006
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 I recommend this paper
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Comments on Related Papers |
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Related Paper: Reconstitution of gamma-secretase activity.
Comment by: Andre Delacourte
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Submitted 10 April 2003
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Posted 13 April 2003
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I recommend this paper
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Related Paper: Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2.
Comment by: Mark Farmery (Disclosure)
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Submitted 15 May 2003
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Posted 15 May 2003
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This is an extremely important paper that, along with recent publications
from Iwatsubo et al., 2003 and Haass et al., 2003,
finally show that the γ-sceretase complex is composed of four
transmembrane proteins: presenillin, nicastrin, Aph-1 and Pen-2. It is a
clear and convincing study that builds on previous work from the same group
and brings together genetic and biochemical evidence for the structure,
function and composition of the γ-sceretase complex in a human cell
model system. Kimberly et al. show that these four components are required
for the maturation and stability of the complex, and the production of
amyloid-β. The challenge now remains to elucidate regulatory mechanisms
and substrate-specificity of the complex and to biochemically reconstitute
the components in an in-vitro system in order to rationally design
inhibitory compounds.
 View all comments by Mark Farmery |
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REAGENTS/MATERIAL:
Genetice screen prepared to find new mutants, alleles and enhancers. Found aph-1 and pen-2 new members of Notch pathway which interact with presenilin genes. RNAi assays preformed by microinjection.
Suppression test performed on lin 12(gf) or lin 12 (intra) phenotypes with aph-1 and pen-2. Vulval structures and anchor cells rated.
Transformation rescue by microinjection of DNA from human or c elegans to generate arrays.
Drosphila cultured cells (Dmel-2)transfected and assayed by Lucerferase reporter assay. gamma secretase activity assayed with/without inhibitor compound E. Sandwich ELISA used for specific Abeta forms. Polyclonal Drosphilia presenilin antibody developed. Cell viability assay by ProCheck.
FUTURE DIRECTION:
Plenty of future directions to take here. The big questions are what does aph-1 do, and could this locus be directly linked to AD, as the mapping experiments hint at. The Notch role is also intriguing and there is enough molecular biology to do to keep a few post-docs busy for the next few years. Watch this space.
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