title: Cellular mechanisms of γ-secretase substrate selection, processing and toxicity.
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.
authors.affiliation: Center for Molecular Biology and Genetics of Neurodegeneration, Departments of Psychiatry and Neuroscience, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Gael
authors.initials: G
authors.lastname: Barthet
authors.forename: Anastasios
authors.initials: A
authors.lastname: Georgakopoulos
authors.forename: Nikolaos K
authors.initials: NK
authors.lastname: Robakis
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D006801:Humans; D053763:Presenilins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D053763:Presenilins; D053829:Amyloid Precursor Protein Secretases