Diverse Functions of γ -secretase: Releasing Signaling Fragments and Deleterious Molecules

Author(s): Sun-Ho Han, Chaeyoung Kim, Inhee Mook-Jung

Journal Name: Current Enzyme Inhibition

Volume 9 , Issue 1 , 2013

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Abstract:

γ-secretase is a pleiotropic intramembrane-cleaving protease. It is a multiprotein complex that comprises presnilin (PS), nicastrin (NCT), presnilin enhancer-2 (Pen-2), and anterior pharynx-defective-1 (Aph-1)—all of which are essential for its proteolytic activity. Promiscuously diverse substrates are susceptible to cleavage by γ-secretase, of which amyloid precursor protein (APP) and notch are the well-characterized substrates. Specifically, APP processing by γ - secretase has garnered much attention, because the generation of amyloidogenic amyloid β peptide (Aβ) is the hallmark of the pathogenesis of Alzheimer’s disease (AD). Thus, the regulatory mechanisms and substrate specificities of γ-secretase proteolytic activity have been studied extensively as therapeutic targets of AD. Further, the processing of other substrates has broad biological implications, releasing an intracellular domain that functions as a signaling molecule. Hence, γ - secretase regulates many physiological functions and pathologies.

We summarize the current literatures on γ-secretase, including its assembly and substrates. Its diverse substrates and the downstream events that are initiated by the release of the intracellular domains of substrates after γ-secretase cleavage are discussed, as is their significance under normal and aberrant physiological conditions. Further, the regulation of γ - secretase activity is broached to yield insights into using this promiscuous enzyme to develop therapeutic agents for AD.

Keywords: γ-secretase, amyloid β-peptide (Aβ), Notch, APP, Alzheimer disease.

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Article Details

VOLUME: 9
ISSUE: 1
Year: 2013
Page: [15 - 27]
Pages: 13
DOI: 10.2174/1573408011309010004

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