γ-secretase

γ-secretase

GS is regulated by layers of control, from subunit composition to associated proteins that may regulate the complex in specific tissues or disease situations, so drugs that influence those components can decrease Aβ as well. Compounds that target γ-secretase include γ-secretase inhibitors (GSIs), Notch-sparing GSIs, and γ-secretase modulators (GSMs). Among these, small-molecule GSIs have been shown to reduce Aβ production.

Previously, γ-secretase (GS) was identified as a multiprotein complex of presenilin, nicastrin (NCT), anterior pharynx-defective 1 (APH-1), and presenilin enhancer 2 (PEN2), and all 4 proteins are reportedly necessary for proteolytic activity (De Strooper,2003; Kimberly andWolfe,2003). This complex typically cleaves type-I transmembrane proteins such as APP, and presenilin harbors the catalytically active site, which is required for the aspartyl protease activity of γ-secretase. Whereas the C-terminal length of (AD) brains (Iwatsubo etal.,1994). Moreover, a class of familial AD has been reported to be caused by genetic mutations of presenilin1 and 2, associated with increased presence of Aβ42 species (Borcheltetal.,1996). These findings indicate that Aβ42 production by γ-secretase plays an important role in the pathogenesis of AD.

GS is regulated by layers of control, from subunit composition to associated proteins that may regulate the complex in specific tissues or disease situations, so drugs that influence those components can decrease Aβ as well. Compounds that target γ-secretase include γ-secretase inhibitors (GSIs), Notch-sparing GSIs, and γ-secretase modulators (GSMs). Among these, small-molecule GSIs have been shown to reduce Aβ production.

Notch was the second GS substrate identified (De Strooper et al., 1999; Ray et al., 1999a; Ray et al., 1999b). Importantly, Notch can act as a proto-oncogene or tumor suppressor in some cancers (Lobry et al., 2011). It is also involved in neural differentiation, which is especially crucial during neural development. All four Notch receptors are GS substrates (Saxena et al., 2001), so any therapeutic that inhibits GS activity completely will also block the action of Notch.

GS regulation is crucial to the maintenance and proliferation of adult neural stem cells, and modulating GS activity could improve cognitive outcomes based on its effect on these specific cell types. While most of the focus of GS modulators has been on its effects on Aβ, altering Notch signaling could also improve cognitive outcomes by maintaining neural stem cells, and Notch-focused therapies still need to be investigated.

GS substrate, to regulate growth cone collapse and recovery in axon path finding through CHL1 processing.

The subcellular localization of γ-secretase is showed to be closely involved in determining the characteristics of its proteolytic activity. In vitro and cell-based assays revealed that the ε-cleavage site of γ-secretase was altered depending on its subcellular localization and pH, the latter being different between the cell surface and endosomes. In addition, the lipid microenvironment surrounding γ-secretase has a large effect on successive γ-cleavage, leading to alterations in the Aβ42 production ratio. With regard to the regulators of the subcellular localization of γ-secretase, several proteins associated with G protein-coupled receptors (GPCRs) have been identified (Thathiah and De Strooper, 2011). GPR3, a constitutively active orphan GPCR, regulates the formation and cell-surface localization of the γ-secretase complex (Thathiah et al., 2009). Other GPCRs, such as the β2-adrenergic receptor and corticotrophin-releasing factor receptor 1 directly associate with the γ-secretase complex, and this agonist-mediated endocytosis causes the cointernalization of γ-secretase to be transported from the cell surface to late endosomes/lysosomes, where γ-secretase activity increases.

Inhibition of Aβ production via cleavage of APP is an appealing strategy, but it has proved unsuccessful in therapeutic trials. BMS 299897, is a γ-secretase inhibitor and reduces Aβ in the brain, plasma and cerebrospinal fluid in vivo. Preclinical of BMS 299897 for Alzheimer's disease was discontinued in USA on 07 Nov 2013. γ-secretase as an enzyme holds more process in AD therapeutics then just canonical inhibitors and modulators. GS is regulated by its subunits and associated proteins, so drugs that influence those components can decrease Aβ as well. Therapeutics can also alter GS trafficking and thereby improve cognition, or move beyond Aβ entirely, effecting Notch and neural stem cells. GS cleavage of DCC, neuroligin, and ephrin control neuronal morphology and function, presenting another avenue by which GS modulation could improve AD pathology. Taken together, GS presents a unique hub for neural processes and an ideal target for AD Therapeutics.

Reference: Kunihiko Kanatsu, Taisuke Tomita. Biological Chemistry’ Just Accepted’ paper ISSN (online) 1437-4315 DOI: 10.1515/hsz-2016-0146

Courtney M.Carroll, Yue-Ming Li, Physiological and pathological roles of the rmgamma-secretase complex, Brain Research Bulletin

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