title: Presenilin 1 regulates pharmacologically distinct gamma -secretase activities. Implications for the role of presenilin in gamma -secretase cleavage.
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 gamma-secretase cleavage that generates the amyloid beta protein (Abeta). It is not clear how PSs regulate gamma-secretase cleavage, but there is evidence that PSs could be either essential cofactors in the gamma-secretase cleavage, gamma-secretase themselves, or regulators of intracellular trafficking that indirectly influence gamma-secretase cleavage. Using presenilin 1 (PS1) mutants that inhibit Abeta production in conjunction with transmembrane domain mutants of the amyloid protein precursor that are cleaved by pharmacologically distinct gamma-secretases, we show that PS1 regulates multiple pharmacologically distinct gamma-secretase activities as well as inducible alpha-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 gamma-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.
authors.affiliation: Mayo Clinic Jacksonville, Department of Pharmacology, Jacksonville, Florida 32224, USA.
authors.forename: M P
authors.initials: MP
authors.lastname: Murphy
authors.forename: S N
authors.initials: SN
authors.lastname: Uljon
authors.forename: P E
authors.initials: PE
authors.lastname: Fraser
authors.forename: A
authors.initials: A
authors.lastname: Fauq
authors.forename: H A
authors.initials: HA
authors.lastname: Lookingbill
authors.forename: K A
authors.initials: KA
authors.lastname: Findlay
authors.forename: T E
authors.initials: TE
authors.lastname: Smith
authors.forename: P A
authors.initials: PA
authors.lastname: Lewis
authors.forename: D C
authors.initials: DC
authors.lastname: McLendon
authors.forename: R
authors.initials: R
authors.lastname: Wang
authors.forename: T E
authors.initials: TE
authors.lastname: Golde
mesh_terms: D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D016466:CHO Cells; D020134:Catalytic Domain; D002460:Cell Line; D006224:Cricetinae; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology*; D008969:Molecular Sequence Data; D053764:Presenilin-1
chemical_list: D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human