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| Mechanisms of disease: Inhibiting | ||||||||||
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The retrieval to endoplasmic reticulum-1 (RER1) protein inhibits 
-secretase activity, making it an attractive target for the development of treatments for Alzheimer's disease.
The -secretase complex cleaves amyloid precursor protein (APP; resulting in the release of amyloid-
, 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 -secretase-complex assembly. This insight might open up new avenues for drug development.
The minimal requirements for the -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 -secretase assembly is still far from understood.
The authors first showed, by co-immunoprecipitation in human cells, that RER1 preferentially interacts with immature uncomplexed NCT, but not with other components of -secretase. Further examination of the interaction between RER1 and NCT showed that this binding is mediated through polar residues of the transmembrane domain of NCT. As it turns out, these residues are also crucial for the binding of APH1 to NCT, which suggests that RER1 and APH1 compete for NCT.
To examine the effects of the interaction between RER1 and NCT, the authors modulated the expression of RER1. Intriguingly, they observed that downregulation of RER1 resulted in increased -secretase-complex formation and increased -secretase activity, whereas upregulation of RER1 resulted in the opposite. That is, the RER1 protein level regulates cellular -secretase activity.
As the authors point out, controlling amyloid- production by modulating -secretase activity is considered a key strategy for the treatment of Alzheimer's disease. The focus of this strategy has mainly been PS, which contains the catalytic site of -secretase. Now, the ectopic inhibition of -secretase activity through RER1 suggests another route to achieve -secretase control.
Asher Mullard
-secretase complex assembly in the early secretory pathway. J. Cell Biol. 176, 629–640 (2007) | Article | PubMed |-Secretase: proteasome of the membrane? Nature Rev. Mol. Cell Biol. 5, 499–504 (2004) | Article | PubMed |
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