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

Presenilins (PSs) are catalytic components of the gamma-secretase proteolytic complexes that produce A beta and cell signaling peptides. gamma-Secretase substrates are mostly membrane-bound peptides derived following proteolytic cleavage of the extracellular domain of type I transmembrane proteins. Recent work reveals that gamma-secretase substrate processing is regulated by proteins termed gamma-secretase substrate recruiting factors (gamma SSRFs) that bridge substrates to gamma-secretase complexes. These factors constitute novel targets for pharmacological control of specific gamma-secretase products, such as A beta and signaling peptides. PS familial Alzheimer's disease (FAD) mutants cause a loss of gamma-secretase cleavage function at epsilon sites of substrates thus inhibiting production of cell signaling peptides while promoting accumulation of uncleaved toxic substrates. Importantly, gamma-secretase inhibitors may cause toxicity in vivo by similar mechanisms. Here we review novel mechanisms that control gamma-secretase substrate selection and cleavage and examine their relevance to AD. (C) 2012 Elsevier Ltd. All rights reserved.