Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Amyloid Precursor Protein Secretases
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Amyloid beta-Peptides / biosynthesis*
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Amyloid beta-Peptides / metabolism
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Amyloid beta-Protein Precursor / metabolism*
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Animals
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Aspartic Acid Endopeptidases
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Cell Line
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Endopeptidases / metabolism
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Gene Expression Regulation
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Humans
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Membrane Proteins / deficiency
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mice
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Mice, Knockout
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Phospholipase D / genetics
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Phospholipase D / metabolism*
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Presenilin-1
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Protein Binding
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Protein Processing, Post-Translational*
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Protein Transport
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trans-Golgi Network / metabolism
Substances
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Membrane Proteins
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PSEN1 protein, human
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Presenilin-1
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Phospholipase D
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phospholipase D1
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Amyloid Precursor Protein Secretases
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Endopeptidases
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Aspartic Acid Endopeptidases
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BACE1 protein, human
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Bace1 protein, mouse