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Prog Neurobiol. 2012 Aug;98(2):166-75. doi: 10.1016/j.pneurobio.2012.05.006. Epub 2012 May 20.

Cellular mechanisms of γ-secretase substrate selection, processing and toxicity.

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1
Center for Molecular Biology and Genetics of Neurodegeneration, Departments of Psychiatry and Neuroscience, Mount Sinai School of Medicine, New York, NY 10029, USA.

Abstract

Presenilins (PSs) are catalytic components of the γ-secretase proteolytic complexes that produce Aβ and cell signaling peptides. γ-Secretase substrates are mostly membrane-bound peptides derived following proteolytic cleavage of the extracellular domain of type I transmembrane proteins. Recent work reveals that γ-secretase substrate processing is regulated by proteins termed γ-secretase substrate recruiting factors (γSSRFs) that bridge substrates to γ-secretase complexes. These factors constitute novel targets for pharmacological control of specific γ-secretase products, such as Aβ and signaling peptides. PS familial Alzheimer's disease (FAD) mutants cause a loss of γ-secretase cleavage function at epsilon sites of substrates thus inhibiting production of cell signaling peptides while promoting accumulation of uncleaved toxic substrates. Importantly, γ-secretase inhibitors may cause toxicity in vivo by similar mechanisms. Here we review novel mechanisms that control γ-secretase substrate selection and cleavage and examine their relevance to AD.

PMID:
22622135
PMCID:
PMC3404154
DOI:
10.1016/j.pneurobio.2012.05.006
[Indexed for MEDLINE]
Free PMC Article
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