Assembly, Trafficking and Function of γ-Secretase

  title={Assembly, Trafficking and Function of $\gamma$-Secretase},
  author={Christoph Kaether and Christian Haass and Harald Steiner},
  journal={Neurodegenerative Diseases},
  pages={275 - 283}
γ-Secretase catalyzes the final cleavage of the β-amyloid precursor protein to generate amyloid-β peptide, the principal component of amyloid plaques in the brains of patients suffering from Alzheimer’s disease. Here, we review the identification of γ-secretase as a protease complex and its assembly and trafficking to its site(s) of cellular function. In reconstitution experiments, γ-secretase was found to be composed of four integral membrane proteins, presenilin (PS), nicastrin (NCT), PEN-2… 
Assembly, maturation, and trafficking of the gamma-secretase complex in Alzheimer's disease.
This review discusses the biology of gamma-secretase, an enigmatic enzyme complex that is responsible for the generation of the amyloid-beta peptide that constitutes theAmyloid plaques of Alzheimer's disease, and synthesizes all of the included topics into an overarching model for the assembly and trafficking of the gamma- secretase complex.
γ-Secretase regulates the α-secretase cleavage of the Alzheimer’s disease, amyloid precursor protein
A feedback regulation from γ-secretase to α- secretase is uncovered and it is shown that γ -secretase inhibition either pharmacologically or by silencing ιsecretase components increases α-secret enzyme cleavage of APP, showing an unexpected consequence on α-cleavage ofAPP.
Structure of γ-Secretase and Its Trimeric Pre-activation Intermediate by Single-particle Electron Microscopy*
The three-dimensional reconstruction of a mature and catalytically active γ-secretase using single-particle cryo-electron microscopy is determined and suggests that the incorporation of PEN-2 might contribute to the maturation of the active site architecture.
In Vivo Reconstitution of γ-Secretase in Drosophila Results in Substrate Specificity
The approach for the first time demonstrates the overall functionality of reconstituted γ-secretase in a multicellular organism and the requirement for substrate-specific factors for efficient in vivo cleavage of certain substrates.
Structure and dynamics of γ-secretase with presenilin 2 compared to presenilin 1
The cryo-electron microscopic data for PS1 is used to develop the first structural and dynamic model of PS2-γ-secretase in the catalytically relevant mature membrane-bound state at ambient temperature, equilibrated by three independent 500 ns molecular dynamics simulations.
SNX15 Regulates Cell Surface Recycling of APP and Aβ Generation
Exogenous expression of human SNX15 in the hippocampal dentate gyrus by adeno-associated virus (AAV) infection can significantly reduce Aβ pathology in the hippocampus and improve short-term working memory in the APPswe/PSEN1dE9 double transgenic AD model mice.
Dysregulation of intracellular trafficking and endosomal sorting in Alzheimer's disease: controversies and unanswered questions.
Recent advances in understanding the regulation of the intracellular sorting of BACE1 and APP are highlighted, how dysregulation of these trafficking events may lead to enhanced generation of the neurotoxic Aβ products in AD is discussed and unresolved questions in the field are highlighted.
Endoplasmic reticulum retention of the γ‐secretase complex component Pen2 by Rer1
Retention in endoplasmic reticulum 1 (Rer1) is identified as a protein that is involved in the retention/retrieval of unassembled Pen2 to the ER and Rer1 is the first identified interaction partner of mammalian transmembrane‐based retention/ retrieval signals.


Reconstitution of γ-secretase activity
The biological activity of γ-secretase is reconstituted by the co-expression of human PS, Nct, APH-1 and PEN-2 in yeast.
The Extreme C Terminus of Presenilin 1 Is Essential for γ-Secretase Complex Assembly and Activity*
The effects of modifications on the C terminus of PS1 on PS1 endoproteolysis, γ-secretase complex assembly, and activity in cells devoid of endogenous PS are investigated and suggest that the PS1 N- and C-terminal fragment intermolecular interactions are independent of an association with nicastrin and Aph-1.
Nicastrin Interacts with γ-Secretase Complex Components via the N-terminal Part of Its Transmembrane Domain*
It is demonstrated that NCT interacts with other γ-secretase complex components via its TMD, and the N-terminal region of the NCT TMD is identified as a functionally important entity of NCT.
Reconstitution of gamma-secretase activity.
The biological activity of gamma-secretase is reconstituted by the co-expression of human PS, Nct, APH-1 and PEN-2 in yeast.
γ-Secretase is a membrane protein complex comprised of presenilin, nicastrin, aph-1, and pen-2
It is shown that Aph-1 and Pen-2, two recently identified membrane proteins genetically linked to γ-secretase, associate directly with presenilin and nicastrin in the active protease complex and coassemble to form the active enzyme in mammalian cells.
Presenilin and nicastrin regulate each other and determine amyloid β-peptide production via complex formation
It is concluded that Nct and PS regulate each other and determine γ-secretase function via complex formation and down-regulation of Nct levels destabilized PS and strongly lowered levels of the high molecular weight PS1 complex.
Uncovering gamma-secretase.
The complete set of genes that is required to generate Abeta from its precursor has now ultimately been identified and genetics paved the way for subsequent biochemical reconstitution studies that demonstrated that gamma-secretase is a protein complex composed of presenilin (PS), nicastrin (NCT), APH-1 and PEN-2.
Photoactivated γ-secretase inhibitors directed to the active site covalently label presenilin 1
Cleavage of amyloid precursor protein (APP) by the β- and γ-secretases generates the amino and carboxy termini, respectively, of the Aβ amyloidogenic peptides Aβ40 and Aβ42—the major constituents of
Presenilin-1 affects trafficking and processing of βAPP and is targeted in a complex with nicastrin to the plasma membrane
It is demonstrated that biologically active GFP-tagged PS1 as well as endogenous PS1 are targeted to the plasma membrane of living cells and suggested a dual function of PS in γ-secretase processing and in trafficking.
γ-Secretase Complex Assembly within the Early Secretory Pathway*
γ-Secretase is an aspartyl protease complex composed of the four core components APH-1, nicastrin (NCT), presenilin (PS), and PEN-2. It catalyzes the final intramembranous cleavage of the