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Title: Random mutagenesis of presenilin-1 identifies novel mutants exclusively generating long amyloid beta-peptides
Authors: Nakaya, Yoshifumi
Yamane, Takuya
Shiraishi, Hirohisa
Wang, Hua-Qin
Matsubara, Etsuro
Sato, Toru
Dolios, Georgia
Wang, Rong
De Strooper, Bart
Shoji, Mikio
Komano, Hiroto
Yanagisawa, Katsuhiko
Ihara, Yasuo
Fraser, Paul
St George-Hyslop, Peter
Nishimura, Masaki # ×
Issue Date: May-2005
Publisher: American Society for Biochemistry and Molecular Biology
Series Title: Journal of Biological Chemistry vol:280 issue:19 pages:19070-7
Abstract: Familial Alzheimer disease-causing mutations in the presenilins increase production of longer pathogenic amyloid beta-peptides (A beta(42/43)) by altering gamma-secretase activity. The mechanism underlying this effect remains unknown, although it has been proposed that heteromeric macromolecular complexes containing presenilins mediate gamma-secretase cleavage of the amyloid beta-precursor protein. Using a random mutagenesis screen of presenilin-1 (PS1) for PS1 endoproteolysis-impairing mutations, we identified five unique mutants, including R278I-PS1 and L435H-PS1, that exclusively generated a high level of A beta43, but did not support physiological PS1 endoproteolysis or A beta40 generation. These mutants did not measurably alter the molecular size or subcellular localization of PS1 complexes. Pharmacological studies indicated that the up-regulation of activity for A beta43 generation by these mutations was not further enhanced by the difluoroketone inhibitor DFK167 and was refractory to inhibition by sulindac sulfide. These results suggest that PS1 mutations can lead to a wide spectrum of changes in the activity and specificity of gamma-secretase and that the effects of PS1 mutations and gamma-secretase inhibitors on the specificity are mediated through a common mechanism.
URI: 
ISSN: 0021-9258
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular Genetics Section (-)
Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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