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

Gael Barthet, Anastasios Georgakopoulos, Nikolaos K. Robakis
Progress in Neurobiology. 2012-08-01; 98(2): 166-175
DOI: 10.1016/j.pneurobio.2012.05.006

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Barthet G(1), Georgakopoulos A, Robakis NK.

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

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.

Copyright © 2012 Elsevier Ltd. All rights reserved.

 

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