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

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.

► Review explores the concept that γ-secretase cleavage is regulated by γ-secretase substrate recruiting factors (γSSRFs).
► γSSRFs are targets for drugs to inhibit specific γ-secretase products.
► Review clarifies roles of gamma (γ) and epsilon (ɛ) γ-secretase cleavages in the production of Aβ and signaling peptides.
► Roles of epsilon (ɛ) γ-secretase cleavage in familial Alzheimer disease (FAD) and neurotoxicity of γ-secretase inhibitors.
► Reviews evidence that presenilin FAD mutations cause loss of γ-secretase cleavage activity inhibiting signaling peptides.