The Presenilins Turned Inside Out: Implications for Their Structures and Functions

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2004 Jan 21

PMID 14732691

Citations 11

Authors

Nazneen N Dewji

Dante Valdez

S J Singer

Affiliations

Soon will be listed here.

Abstract

The presenilin (PS) proteins are polytopic integral membrane proteins that are critically involved in the development of Alzheimer's disease. The topography of the PS molecule in the endoplasmic reticulum membrane is widely accepted as exhibiting eight-hydrophobic-transmembrane (8-TM) helices. We have previously provided evidence, however, that the intact PS molecule is also present in the cell surface where it exhibits exclusively a 7-TM topography, which differs in significant structural features from the 8-TM model. This evidence, however, has been disparaged and generally rejected by researchers in Alzheimer's disease. The 7-TM model is definitively demonstrated in the present study for PS-1 at the surfaces of PS-1-transfected cells and for endogenous PS-1 at the surfaces of untransfected cells, by immunofluorescence studies using mAbs. These studies force substantial revision of current views of the structural and functional properties of the PS proteins.

Citing Articles

Peptides of presenilin-1 bind the amyloid precursor protein ectodomain and offer a novel and specific therapeutic approach to reduce ß-amyloid in Alzheimer's disease.

Dewji N, Singer S, Masliah E, Rockenstein E, Kim M, Harber M PLoS One. 2015; 10(4):e0122451.

PMID: 25923432 PMC: 4414571. DOI: 10.1371/journal.pone.0122451.

Intraperitoneal injection of JNK-specific inhibitor SP600125 inhibits the expression of presenilin-1 and Notch signaling in mouse brain without induction of apoptosis.

Rahman M, Zhang Z, Mody A, Su D, Das H Brain Res. 2012; 1448:117-28.

PMID: 22353755 PMC: 3310381. DOI: 10.1016/j.brainres.2012.01.066.

Structural investigation of the C-terminal catalytic fragment of presenilin 1.

Sobhanifar S, Schneider B, Lohr F, Gottstein D, Ikeya T, Mlynarczyk K Proc Natl Acad Sci U S A. 2010; 107(21):9644-9.

PMID: 20445084 PMC: 2906861. DOI: 10.1073/pnas.1000778107.

BACE and gamma-secretase characterization and their sorting as therapeutic targets to reduce amyloidogenesis.

Marks N, Berg M Neurochem Res. 2009; 35(2):181-210.

PMID: 19760173 DOI: 10.1007/s11064-009-0054-1.

Antibody library-based tumor endothelial cells surface proteomic functional screen reveals migration-stimulating factor as an anti-angiogenic target.

Hu H, Ran Y, Zhang Y, Zhou Z, Harris S, Yu L Mol Cell Proteomics. 2009; 8(4):816-26.

PMID: 19117829 PMC: 2667360. DOI: 10.1074/mcp.M800331-MCP200.

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