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γ‐Secretase/presenilin inhibitors for Alzheimer's disease phenocopy Notch mutations in Drosophila
Author(s) -
Micchelli Craig A.,
Esler William P.,
Kimberly W. Taylor,
Jack Christine,
Berezovska Oksana,
Kornilova Anna,
Hyman Bradley T.,
Perrimon Norbert,
Wolfe Michael S.
Publication year - 2003
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-0394fje
Subject(s) - phenocopy , presenilin , gamma secretase , amyloid precursor protein secretase , biology , amyloid precursor protein , notch signaling pathway , microbiology and biotechnology , transmembrane protein , transgene , in vivo , signal transduction , amyloid beta , amyloid (mycology) , receptor , alzheimer's disease , genetics , biochemistry , gene , disease , phenotype , medicine , peptide , botany
Signaling from the Notch (N) receptor is essential for proper cell‐fate determinations and tissue patterning in all metazoans. N signaling requires a presenilin (PS)‐dependent transmembrane‐cleaving activity that is closely related or identical to the γ‐secretase proteolysis of the amyloid‐β precursor protein (APP) involved in Alzheimer's disease pathogenesis. Here, we show that N‐[N‐(3,5‐difluorophenacetyl)‐L‐alanyl]‐(S)‐phenylglycine t‐butyl ester, a potent γ‐secretase inhibitor reported to reduce amyloid‐β levels in transgenic mice, prevents N processing, translocation, and signaling in cell culture. This compound also induces developmental defects in Drosophila remarkably similar to those caused by genetic reduction of N. The appearance of this phenocopy depends on the timing and dose of compound exposure, and effects on N‐dependent signaling molecules established its biochemical mechanism of action in vivo . Other γ‐secretase inhibitors caused similar effects. Thus, the three‐dimensional structure of the drug‐binding site(s) in Drosophila γ‐secretase is remarkably conserved vis‐à‐vis the same site(s) in the mammalian enzyme. These results show that genetics and developmental biology can help elucidate the in vivo site of action of pharmacological agents and suggest that organisms such as Drosophila may be used as simple models for in vivo prescreening of drug candidates.