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Identification of novel ?-secretase-associated proteins in detergent-resistant membranes from brain.

ABSTRACT: In Alzheimer disease, oligomeric amyloid ?-peptide (A?) species lead to synapse loss and neuronal death. ?-Secretase, the transmembrane protease complex that mediates the final catalytic step that liberates A? from its precursor protein (APP), has a multitude of substrates, and therapeutics aimed at reducing A? production should ideally be specific for APP cleavage. It has been shown that APP can be processed in lipid rafts, and ?-secretase-associated proteins can affect A? production. Here, we use a biotinylated inhibitor for affinity purification of ?-secretase and associated proteins and mass spectrometry for identification of the purified proteins, and we identify novel ?-secretase-associated proteins in detergent-resistant membranes from brain. Furthermore, we show by small interfering RNA-mediated knockdown of gene expression that a subset of the ?-secretase-associated proteins, in particular voltage-dependent anion channel 1 (VDAC1) and contactin-associated protein 1 (CNTNAP1), reduced A? production (A?40 and A?42) by around 70%, whereas knockdown of presenilin 1, one of the essential ?-secretase complex components, reduced A? production by 50%. Importantly, these proteins had a less pronounced effect on Notch processing. We conclude that VDAC1 and CNTNAP1 associate with ?-secretase in detergent-resistant membranes and affect APP processing and suggest that molecules that interfere with this interaction could be of therapeutic use for Alzheimer disease.

SUBMITTER: Hur JY

PROVIDER: S-EPMC3320946 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Identification of novel γ-secretase-associated proteins in detergent-resistant membranes from brain.

Hur Ji-Yeun JY Teranishi Yasuhiro Y Kihara Takahiro T Yamamoto Natsuko Goto NG Inoue Mitsuhiro M Hosia Waltteri W Hashimoto Masakazu M Winblad Bengt B Frykman Susanne S Tjernberg Lars O LO

The Journal of biological chemistry 20120207 15

In Alzheimer disease, oligomeric amyloid β-peptide (Aβ) species lead to synapse loss and neuronal death. γ-Secretase, the transmembrane protease complex that mediates the final catalytic step that liberates Aβ from its precursor protein (APP), has a multitude of substrates, and therapeutics aimed at reducing Aβ production should ideally be specific for APP cleavage. It has been shown that APP can be processed in lipid rafts, and γ-secretase-associated proteins can affect Aβ production. Here, we ...[more]

PMID: 22315232

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Project description:A large body of evidence from the past decade supports the existence, in membrane from animal and yeast cells, of functional microdomains playing important roles in protein sorting, signal transduction, or infection by pathogens. In plants, as previously observed for animal microdomains, detergent-resistant fractions, enriched in sphingolipids and sterols, were isolated from plasma membrane. A characterization of their proteic content revealed their enrichment in proteins involved in signaling and response to biotic and abiotic stress and cell trafficking suggesting that these domains were likely to be involved in such physiological processes. In the present study, we used (14)N/(15)N metabolic labeling to compare, using a global quantitative proteomics approach, the content of tobacco detergent-resistant membranes extracted from cells treated or not with cryptogein, an elicitor of defense reaction. To analyze the data, we developed a software allowing an automatic quantification of the proteins identified. The results obtained indicate that, although the association to detergent-resistant membranes of most proteins remained unchanged upon cryptogein treatment, five proteins had their relative abundance modified. Four proteins related to cell trafficking (four dynamins) were less abundant in the detergent-resistant membrane fraction after cryptogein treatment, whereas one signaling protein (a 14-3-3 protein) was enriched. This analysis indicates that plant microdomains could, like their animal counterpart, play a role in the early signaling process underlying the setup of defense reaction. Furthermore proteins identified as differentially associated to tobacco detergent-resistant membranes after cryptogein challenge are involved in signaling and vesicular trafficking as already observed in similar studies performed in animal cells upon biological stimuli. This suggests that the ways by which the dynamic association of proteins to microdomains could participate in the regulation of the signaling process may be conserved between plant and animals.

Dataset Information

Identification of novel ?-secretase-associated proteins in detergent-resistant membranes from brain.

Publications

Identification of novel γ-secretase-associated proteins in detergent-resistant membranes from brain.

Similar Datasets

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