Presenilin-1 uses phospholipase D1 as a negative regulator of beta-amyloid formation.
Presenilin (PS1/PS2) is a major component of gamma-secretase, the activity that mediates proteolysis of beta-amyloid precursor protein to generate beta-amyloid (Abeta). Here we demonstrate that PS1, through its loop region, binds to phospholipase D1 (PLD1), thereby recruiting it to the Golgi/trans-Golgi network. Overexpression of wild-type PLD1 reduces Abeta generation. Conversely, down-regulation of endogenous PLD1 by small hairpin RNA elevates Abeta production. The Abeta-lowering effect of PLD1 is independent of its ability to promote vesicular budding of beta-amyloid precursor protein. The data indicate that overexpression of PLD1 decreases, and down-regulation of PLD1 increases, the catalytic activity, and the association of the subunits, of gamma-secretase.
Cai
Dongming
D
Laboratory of Molecular and Cellular Neuroscience, and Fisher Center for Research on Alzheimer Disease, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
Netzer
William J
WJ
Zhong
Minghao
M
Lin
Yixin
Y
Du
Guangwei
G
Frohman
Michael
M
Foster
David A
DA
Sisodia
Sangram S
SS
Xu
Huaxi
H
Gorelick
Fred S
FS
Greengard
Paul
P
D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D002460:Cell Line; D010450:Endopeptidases / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010739:Phospholipase D / Q000235:genetics / Q000378:metabolism*; D053764:Presenilin-1; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D021601:trans-Golgi Network / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D010739:Phospholipase D; C106801:phospholipase D1; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse