title: A presenilin 1 mutation associated with familial frontotemporal dementia inhibits gamma-secretase cleavage of APP and notch.
abstract: A novel presenilin 1 mutation, insR352, associated with a frontal temporal dementia phenotype has been identified (E. A. Rogaeva et al., 2001, Neurology 57, 621-625). This mutation does not increase Abeta42 levels, but instead acts as dominant negative presenilin, decreasing amyloid beta protein (Abeta) production by inhibiting gamma-secretase cleavage of the Abeta precursor. The distinct clinical phenotype associated with this mutation suggests that chronic partial inhibition of gamma-secretase activity may result in neurodegeneration.
authors.affiliation: Department of Neuroscience and Pharmacology, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, Florida 32224, USA.
authors.forename: Zareen
authors.initials: Z
authors.lastname: Amtul
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Lewis
authors.forename: Sian
authors.initials: S
authors.lastname: Piper
authors.forename: Richard
authors.initials: R
authors.lastname: Crook
authors.forename: Matt
authors.initials: M
authors.lastname: Baker
authors.forename: Kirk
authors.initials: K
authors.lastname: Findlay
authors.forename: Andrew
authors.initials: A
authors.lastname: Singleton
authors.forename: Marion
authors.initials: M
authors.lastname: Hogg
authors.forename: Linda
authors.initials: L
authors.lastname: Younkin
authors.forename: Steven G
authors.initials: SG
authors.lastname: Younkin
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: Michael
authors.initials: M
authors.lastname: Hutton
authors.forename: Bradley F
authors.initials: BF
authors.lastname: Boeve
authors.forename: David
authors.initials: D
authors.lastname: Tang-Wai
authors.forename: Todd E
authors.initials: TE
authors.lastname: Golde
mesh_terms: D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003704:Dementia / Q000235:genetics* / Q000378:metabolism*; D010450:Endopeptidases / Q000378:metabolism*; D005910:Glioma; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D010641:Phenotype; D053764:Presenilin-1; D051880:Receptors, Notch; D014407:Tumor Cells, Cultured
chemical_list: D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; D053764:Presenilin-1; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases