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A novel mechanism for the regulation of amyloid precursor protein metabolism.

ABSTRACT: 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.

SUBMITTER: Chen Q

PROVIDER: S-EPMC2173011 | biostudies-literature | 2002 Jul

REPOSITORIES: biostudies-literature

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A novel mechanism for the regulation of amyloid precursor protein metabolism.

Chen Qi Q Kimura Hideo H Schubert David D

The Journal of cell biology 20020701 1

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 expressi ...[more]

PMID: 12093789

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Project description:Gangliosides are important players for controlling neuronal function and are directly involved in AD pathology. They are among the most potent stimulators of A? production, are enriched in amyloid plaques and bind amyloid beta (A?). However, the molecular mechanisms linking gangliosides with AD are unknown. Here we identified the previously unknown function of the amyloid precursor protein (APP), specifically its cleavage products A? and the APP intracellular domain (AICD), of regulating GD3-synthase (GD3S). Since GD3S is the key enzyme converting a- to b-series gangliosides, it therefore plays a major role in controlling the levels of major brain gangliosides. This regulation occurs by two separate and additive mechanisms. The first mechanism directly targets the enzymatic activity of GD3S: Upon binding of A? to the ganglioside GM3, the immediate substrate of the GD3S, enzymatic turnover of GM3 by GD3S was strongly reduced. The second mechanism targets GD3S expression. APP cleavage results, in addition to A? release, in the release of AICD, a known candidate for gene transcriptional regulation. AICD strongly down regulated GD3S transcription and knock-in of an AICD deletion mutant of APP in vivo, or knock-down of Fe65 in neuroblastoma cells, was sufficient to abrogate normal GD3S functionality. Equally, knock-out of the presenilin genes, presenilin 1 and presenilin 2, essential for A? and AICD production, or of APP itself, increased GD3S activity and expression and consequently resulted in a major shift of a- to b-series gangliosides. In addition to GD3S regulation by APP processing, gangliosides in turn altered APP cleavage. GM3 decreased, whereas the ganglioside GD3, the GD3S product, increased A? production, resulting in a regulatory feedback cycle, directly linking ganglioside metabolism with APP processing and A? generation. A central aspect of this homeostatic control is the reduction of GD3S activity via an A?-GM3 complex and AICD-mediated repression of GD3S transcription.

Dataset Information

A novel mechanism for the regulation of amyloid precursor protein metabolism.

Publications

A novel mechanism for the regulation of amyloid precursor protein metabolism.

Similar Datasets

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