A novel mechanism for the regulation of amyloid precursor protein metabolism.
Modifier of cell adhesion protein (MOCA; previously called presenilin [PS] binding protein) is a DOCK180-related molecule, which interacts with PS1 and PS2, is localized to brain areas involved in Alzheimer's disease (AD) pathology, and is lost from the soluble fraction of sporadic Alzheimer's disease (AD) brains. Because PS1 has been associated with gamma-secretase activity, MOCA may be involved in the regulation of beta-amyloid precursor protein (APP) processing. Here we show that the expression of MOCA decreases both APP and amyloid beta-peptide secretion and lowers the rate of cell-substratum adhesion. In contrast, MOCA does not lower the secretion of amyloid precursor-like protein (APLP) or several additional type 1 membrane proteins. The phenotypic changes caused by MOCA are due to an acceleration in the rate of intracellular APP degradation. The effect of MOCA expression on the secretion of APP and cellular adhesion is reversed by proteasome inhibitors, suggesting that MOCA directs nascent APP to proteasomes for destruction. It is concluded that MOCA plays a major role in APP metabolism and that the effect of MOCA on APP secretion and cell adhesion is a downstream consequence of MOCA-directed APP catabolism. This is a new mechanism by which the expression of APP is regulated.
Chen
Qi
Q
Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Kimura
Hideo
H
Schubert
David
D
D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis*; D000818:Animals; D001426:Bacterial Proteins / Q000096:biosynthesis*; D015152:Blotting, Northern; D015153:Blotting, Western; D002448:Cell Adhesion; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D007797:Laminin / Q000378:metabolism; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D009097:Multienzyme Complexes / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001426:Bacterial Proteins; D007797:Laminin; C083182:MocA protein, Bacteroides fragilis; D009097:Multienzyme Complexes; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex