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O1–02–07: Different actions of dipeptidic compounds on presenilins define the enzyme specificity of γ–secretase inhibitor
Author(s) -
Tomita Taisuke,
Takahashi Yasuko,
Fuwa Haruhiko,
Konno Yu,
Morohashi Yuichi,
Kan Toshiyuki,
Sugimoto Yasuaki,
Fukuyama Tohru,
Sasaki Makoto,
Natsugari Hideaki,
Iwatsubo Takeshi
Publication year - 2006
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2006.05.259
Subject(s) - nicastrin , chemistry , presenilin , transition state analog , enzyme , transmembrane domain , cleavage (geology) , photoaffinity labeling , stereochemistry , biochemistry , active site , binding site , receptor , biology , alzheimer's disease , paleontology , fracture (geology) , medicine , disease , pathology
accumulates as full-length protein. Objectives: Three possibilities are being tested that could explain the attenuated A 42-response of PS1Exon9. (i) The attenuated A 42-response is caused by lack of endoproteolytic cleavage, or (ii) is specifically associated with the S290C mutation, or (iii) resides in the 291-319 deletion or its conformational effects on regions flanking exon 9. Methods: CHO cell lines with stable overexpression of WT-PS1 or various PS-1 mutants are being compared in their response to the A 42-lowering NSAID sulindac sulfide. Results: CHO cells overexpressing WT-PS1 or mutants PS1Exon9, S290C, M292D and 291-319 have been created. M292D suppresses endoproteolytic cleavage but is otherwise fully functional in -secretase cleavage. Surprisingly, we found that the S290C mutation alone did not cause increased A 42 production indicating that the pathogenic effect of PS1Exon9 is a consequence of the combined action of the S290C mutation and the 291-319 deletion. Accordingly, the S290C mutation behaved similar to WT-PS1 and was not responsible for the blunted A 42-response of PS1Exon9 after sulindac sulfide treatment. Ongoing studies further aim to clarify whether lack of endoproteolysis or the 291-319 deletion underlie the attenuated A 42-response of PS1Exon9. Conclusions: These studies should resolve the molecular basis for the attenuated A 42-response of the PS1Exon9 mutation. They may further lead to definition of a critical region within PS1 that is required for the A 42-lowering activity of certain NSAIDs.