期刊
PROGRESS IN NEUROBIOLOGY
卷 98, 期 2, 页码 166-175出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.pneurobio.2012.05.006
关键词
Alzheimer's disease; Presenilin; FAD mutations cause loss of gamma-secretase activity; gamma-Secretase substrate recruiting factors (gamma SSRFs); Metalloproteinases; ADAMs; Toxic substrates; gamma-Secretase-produced signaling peptides
资金
- NIH [AG-17926, AG-08200, NS 047229, P50AG05138]
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.
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