Presenilin 1 regulates pharmacologically distinct γ-secretase activities: Implications for the role of presenilin in γ-secretase cleavage

M. Paul Murphy, Sacha N. Uljon, Paul E. Fraser, Abdul Fauq, Hilary A. Lookingbill, Kirk A. Findlay, Tawnya E. Smith, Patrick A. Lewis, D. Chris McLendon, Rong Wang, Todd E. Golde

Research output: Contribution to journalArticlepeer-review

91 Scopus citations

Abstract

Presenilins (PSs) are polytopic membrane proteins that have been implicated as potential therapeutic targets in Alzheimer's disease because of their role in regulating the γ-secretase cleavage that generates the amyloid β protein (Aβ). It is not clear how PSs regulate γ-secretase cleavage, but there is evidence that PSs could be either essential cofactors in the γ-secretase cleavage, γ-secretase themselves, or regulators of intracellular trafficking that indirectly influence γ-secretase cleavage. Using presenilin 1 (PS1) mutants that inhibit Aβ production in conjunction with transmembrane domain mutants of the amyloid protein precursor that are cleaved by pharmacologically distinct γ-secretases, we show that PS1 regulates multiple pharmacologically distinct γ-secretase activities as well as inducible α-secretase activity. It is likely that PS1 acts indirectly to regulate these activities (as in a trafficking or chaperone role), because these data indicate that for PS1 to be γ-secretase it must either have multiple active sites or exist in a variety of catalytically active forms that are altered to an equivalent extent by the mutations we have studied.

Original languageEnglish
Pages (from-to)26277-26284
Number of pages8
JournalJournal of Biological Chemistry
Volume275
Issue number34
DOIs
StatePublished - 25 Aug 2000
Externally publishedYes

Fingerprint

Dive into the research topics of 'Presenilin 1 regulates pharmacologically distinct γ-secretase activities: Implications for the role of presenilin in γ-secretase cleavage'. Together they form a unique fingerprint.

Cite this