Gamma-secretase/presenilin inhibitors for Alzheimer's disease phenocopy Notch mutations in Drosophila.
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 gamma-secretase proteolysis of the amyloid-beta 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 gamma-secretase inhibitor reported to reduce amyloid-beta 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 gamma-secretase inhibitors caused similar effects. Thus, the three-dimensional structure of the drug-binding site(s) in Drosophila gamma-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.
Micchelli
Craig A
CA
Department of Genetics, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, USA.
Esler
William P
WP
Kimberly
W Taylor
WT
Jack
Christine
C
Berezovska
Oksana
O
Kornilova
Anna
A
Hyman
Bradley T
BT
Perrimon
Norbert
N
Wolfe
Michael S
MS
D021581:Active Transport, Cell Nucleus; D000544:Alzheimer Disease / Q000201:enzymology; D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D004151:Dipeptides / Q000494:pharmacology*; D004330:Drosophila / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D029721:Drosophila Proteins; D010450:Endopeptidases; D007700:Kinetics; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D053763:Presenilins; D011480:Protease Inhibitors / Q000494:pharmacology*; D051880:Receptors, Notch; D015398:Signal Transduction; D014921:Wings, Animal / Q000033:anatomy & histology / Q000196:embryology
D004151:Dipeptides; D029721:Drosophila Proteins; D008565:Membrane Proteins; C497759:N protein, Drosophila; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D053763:Presenilins; D011480:Protease Inhibitors; C106427:Psn protein, Drosophila; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases