Presenilin: Running with Scissors in the Membrane

Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Cell (Impact Factor: 32.24). 11/2007; 131(2):215-21. DOI: 10.1016/j.cell.2007.10.012
Source: PubMed


The presenilin-containing gamma-secretase complex is an unusual membrane-embedded protease that processes a wide variety of integral membrane proteins, clearing protein stubs from the lipid bilayer and participating in critical signaling pathways. The protease is also central to Alzheimer's disease and certain cancers and is therefore an important therapeutic target. Here we highlight recent progress in deciphering the role of presenilin/gamma-secretase in biology and medicine and pose key questions for future study.

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    • "Mutations in the APP protein or the γ-secretases cause familial AD, and the mutations direct the APP cleavage towards the Aβ42 peptide production, that predominates in cerebral plaques. Aβ42 peptide is more hydrophobic and thus more prone to fibril formation (Selkoe and Wolfe 2007) and increasing evidence suggests that small oligomers of Aβ are the most toxic species (Hartley et al. 1999; McLean et al. 1999). "
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    ABSTRACT: Alzheimer's disease (AD) is the most common neurodegenerative disease, characterized by deposits of amyloid-β (Aβ) peptides. However the underlying molecular mechanisms of neuron cell dysfunction and cell death in AD still remain poorly understood. Yeast Saccharomyces cerevisiae shares many conserved biological processes with all eukaryotic cells, including human neurons. Thanks to relatively simple and quick genetic and environmental manipulations, the large knowledge base and data collections, this organism has become a valuable tool to unravel fundamental intracellular mechanisms underlying neurodegeneration. In this study, we have used yeast as a model system to study the effects of intracellular Aβ peptides and we found that cells constitutively producing native Aβ directed to the secretory pathway exhibited a lower growth rate, lower biomass yield, lower respiratory rate, increased oxidative stress, hallmarks of mitochondrial dysfunction and ubiquitin-proteasome system dysfunction. These findings are relevant for better understanding the role of Aβ in cell stress and cell damage. © FEMS 2015. All rights reserved. For permissions, please e-mail:
    FEMS Yeast Research 07/2015; 15(6). DOI:10.1093/femsyr/fov061 · 2.82 Impact Factor
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    • "The β-secretase is also called BACE1 (β-site amyloid precursor protein cleaving enzyme 1), which is an important enzyme in development of AD pathology. BACE1 cleaves transmembrane APP between residues 671 and 672, and carboxy-terminal fragment of APP is cleaved by γ-secretase, facilitating intramembrane proteolysis by the presenilin 1 (PSEN1) and presenilin 2 (PSEN2) [14, 15]. Subsequently the small 4 kilodalton of amyloid-Aβ1-40 and Aβ1-42 is generated by sequential β and γ-secretase cleavage of APP. "
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    ABSTRACT: The β-site APP cleaving enzyme 1 (BACE1) is an important target for causing Alzheimer's disease (AD), due to the brain deposition peptide amyloid beta (Aβ) require cleavages of amyloid precursor protein (APP) by BACE1 and γ-secretase, but treatments of AD still have side effect in recent therapy. This study utilizes the world largest traditional Chinese medicine (TCM) database and database screening to provide potential BACE1 inhibited compound. Molecular dynamics (MD) simulation was carried out to observe the dynamics structure after ligand binding. We found that Triptofordin B1 has less toxicity than pyrimidine analogue, which has more potent binding affinity with BACE1. For trajectory analysis, all conformations are tending to be stable during 5000 ps simulation time. In dynamic protein validation, the residues of binding region are still stable after MD simulation. For snapshot comparison, we found that Triptofordin B1 could reduce the binding cavity; the results reveal that Triptofordin B1 could bind to BACE1 and better than control, which could be used as potential lead drug to design novel BACE1 inhibitor for AD therapy.
    BioMed Research International 05/2014; 2014(3):741703. DOI:10.1155/2014/741703 · 3.17 Impact Factor
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    • "γ-Secretase is also an aspartyl protease, although it is a complex of four integral membrane proteins and completely unrelated to soluble or membrane-tethered proteases [24]. Nevertheless, inhibitors of γ-secretase were more easily identified and several of these advanced into the clinic much more quickly than inhibitors of BACE1. "
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    ABSTRACT: Brain deposition of the amyloid beta-protein (A β ) and tau are characteristic features in Alzheimer's disease (AD). Mutations in the A β precursor protein (APP) and a protease involved in A β production from APP strongly argue for a pathogenic role of A β in AD, while mutations in tau are associated with related disorders collectively called frontotemporal lobar degeneration (FTLD). Despite intense effort, therapeutic strategies that target A β or tau have not yet yielded medications, suggesting that alternative approaches should be pursued. In recent years, our laboratory has studied the role of mRNA in AD and FTLD, specifically those encoding tau and the A β -producing protease BACE1. As many FTLD-causing tau mutations destabilize a hairpin structure that regulates RNA splicing, we have targeted this structure with small molecules, antisense oligonucleotides, and small molecule-antisense conjugates. We have also discovered that microRNA interaction with the 3'-untranslated region of tau regulates tau expression. Regarding BACE1, we found that alternative splicing leads to inactive splice isoforms and antisense oligonucleotides shift splicing toward these inactive isoforms to decrease A β production. In addition, a G-quadruplex structure in the BACE1 mRNA plays a role in splice regulation. The prospects for targeting tau and BACE1 mRNAs as therapeutic strategies will be discussed.
    04/2014; 2014(5):757549. DOI:10.1155/2014/757549
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