A presenilin 1 mutation associated with familial frontotemporal dementia inhibits gamma-secretase cleavage of APP and notch.
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.
Amtul
Zareen
Z
Department of Neuroscience and Pharmacology, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, Florida 32224, USA.
Lewis
Patrick A
PA
Piper
Sian
S
Crook
Richard
R
Baker
Matt
M
Findlay
Kirk
K
Singleton
Andrew
A
Hogg
Marion
M
Younkin
Linda
L
Younkin
Steven G
SG
Hardy
John
J
Hutton
Michael
M
Boeve
Bradley F
BF
Tang-Wai
David
D
Golde
Todd E
TE
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
D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; D053764:Presenilin-1; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases