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Mechanisms of disease

Inhibiting γ-secretase activity

Nature Reviews Molecular Cell Biology volume 8, pages 272–273 (2007)Cite this article

The γ-secretase complex cleaves amyloid precursor protein (APP; resulting in the release of amyloid-β, a peptide that possibly causes Alzheimer's disease), Notch and other transmembrane proteins. Now, Spasic and colleagues identify retrieval to endoplasmic reticulum-1 (RER1) as an ectopic inhibitor of γ-secretase-complex assembly. This insight might open up new avenues for drug development.

The minimal requirements for the γ-secretase complex are the transmembrane proteins nicastrin (NCT), anterior pharynx defective-1 (APH1), presenilin (PS) and PS enhancer-2 (PEN2). A widely accepted theory of assembly is that NCT and APH1 first form a subcomplex to which PS and PEN2, or perhaps PS–PEN2, are subsequently added. But the full mechanism of γ-secretase assembly is still far from understood.

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References

ORIGINAL RESEARCH PAPER

  1. Spasic, D. et al. Rer1p competes with APH-1 for binding to nicastrin and regulates γ-secretase complex assembly in the early secretory pathway. J. Cell Biol. 176, 629–640 (2007)

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FURTHER READING

  1. Kopan, R. & Ilagan, M. X. G. γ-Secretase: proteasome of the membrane? Nature Rev. Mol. Cell Biol. 5, 499–504 (2004)

    Article  CAS  Google Scholar 

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Authors
  1. Asher Mullard
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Mullard, A. Inhibiting γ-secretase activity. Nat Rev Mol Cell Biol 8, 272–273 (2007). https://doi.org/10.1038/nrm2156

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  • DOI: https://doi.org/10.1038/nrm2156

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