Assembly, Trafficking and Function of γ-Secretase

@article{Kaether2006AssemblyTA,
  title={Assembly, Trafficking and Function of $\gamma$-Secretase},
  author={Christoph Kaether and Christian Haass and Harald Steiner},
  journal={Neurodegenerative Diseases},
  year={2006},
  volume={3},
  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… 
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133 Citations
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133 Citations

Assembly, maturation, and trafficking of the gamma-secretase complex in Alzheimer's disease.
TLDR
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.
Contribution of the Presenilins in the cell biology, structure and function of γ-secretase.
γ-Secretase regulates the α-secretase cleavage of the Alzheimer’s disease, amyloid precursor protein
TLDR
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*
TLDR
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
TLDR
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.
Biogenesis and processing of the amyloid precursor protein in the early secretory pathway.
Structure and dynamics of γ-secretase with presenilin 2 compared to presenilin 1
TLDR
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
TLDR
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.
TLDR
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
TLDR
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.
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References

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TLDR
The biological activity of γ-secretase is reconstituted by the co-expression of human PS, Nct, APH-1 and PEN-2 in yeast.
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TLDR
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.
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TLDR
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TLDR
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TLDR
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TLDR
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TLDR
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TLDR
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