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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    • "However, according to the amyloid hypothesis, the highly aggregative family of Ab peptides plays a crucial role in the development of the disease (Hardy & Higgins, 1992). Ab peptides are released as a result of a dual proteolytic digestion of the type 1 transmembranal amyloid precursor protein (APP) by the b-secretase (BACE) and c-secretase proteolytic complex which is composed of presenilin 1, presenilin 2 (PS1 and PS2, respectively), presenilin enhancer 2 (Pen-2), nicastrin, and the anterior pharynx defective 1 (APH-1) (Selkoe & Wolfe, 2007). Shortly after translation, PS1 undergoes a rapid auto-cleavage to generate the PS1 N-terminal domain (NTF) and C-terminal domain (CTF) (Thinakaran et al, 1996). "
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    ABSTRACT: Do different neurodegenerative maladies emanate from the failure of a mutual protein folding mechanism? We have addressed this question by comparing mutational patterns that are linked to the manifestation of distinct neurodegenerative disorders and identified similar neurodegeneration-linked proline substitutions in the prion protein and in presenilin 1 that underlie the development of a prion disorder and of familial Alzheimer's disease (fAD), respectively. These substitutions were found to prevent the endoplasmic reticulum (ER)-resident chaperone, cyclophilin B, from assisting presenilin 1 to fold properly, leading to its aggregation, deposition in the ER, reduction of c-secretase activity, and impaired mito-chondrial distribution and function. Similarly, reduced quantities of the processed, active presenilin 1 were observed in brains of cyclophilin B knockout mice. These discoveries imply that reduced cyclophilin activity contributes to the development of distinct neurodegenerative disorders, propose a novel mechanism for the development of certain fAD cases, and support the emerging theme that this disorder can stem from aberrant presenilin 1 function. This study also points at ER chaperones as targets for the development of counter-neurodegeneration therapies.
    The EMBO Journal 10/2015; DOI:10.15252/embj.201592042 · 10.43 Impact Factor
    • "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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    • "Best studied are the roles of c-secretases in the processing of the amyloid precursor protein (APP) and the secretion of the neurotoxic amyloid b (Ab) peptides in the context of Alzheimer disease. However, other substrates, including Notch, N-cadherin and ErbB4, link csecretase activities to development, cancer and immunity (De Strooper and Annaert, 2010; Selkoe and Wolfe, 2007). Presenilin 1 (PS1), nicastrin (NCT), presenilin enhancer 2 (PEN-2) and anterior pharynx defective 1A (APH-1A) assemble in a tetrameric complex (Fig. 1A) (De Strooper, 2003) and PS1 autoproteolysis results in an active pentameric c-secretase (Thinakaran et al., 1996), in which the catalytic center is structured at the interface between the N-terminal and the Cterminal fragments of PS1 (NTF and CTF respectively) (Esler et al., 2000; Li et al., 2013; Li et al., 2000; Wolfe et al., 1999) and connected to the intracellular aqueous environment (Sato et al., 2006; Tolia et al., 2006). "
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    ABSTRACT: The structure and function of the γ-secretase proteases are of vast interest because of their critical roles in cellular and disease processes. We established a novel purification protocol for γ-secretase complex that involves a conformation and complex-specific nanobody, yielding highly pure and active enzyme. Using single particle electron microscopy, we analyzed the γ-secretase structure and its conformational variability. Under steady state conditions the complex adopts three major conformations, which are different in overall compactness and relative position of the nicastrin ectodomain. Occupancy of the active or substrate binding sites by inhibitors differentially stabilize sub-populations of particles with compact conformations, whereas a Familial Alzheimer Disease-linked mutation results in enrichment of extended-conformation complexes with increased flexibility. Our study presents the γ-secretase complex as a dynamic population of inter-converting conformations, involving rearrangements at the nanometer scale and high level of structural interdependence between subunits. The fact that protease inhibition or clinical mutations, which affect Aβ generation, enrich for particular subpopulations of conformers indicates the functional relevance of the observed dynamic changes, which are likely instrumental for highly allosteric behavior of the enzyme.
    Journal of Cell Science 12/2014; 128(3). DOI:10.1242/jcs.164384 · 5.43 Impact Factor
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