Presenilins and gamma-secretase inhibitors affect intracellular trafficking and cell surface localization of the gamma-secretase complex components

The Journal of Biological Chemistry
Hong WangHuaxi Xu

Abstract

The intramembranous cleavage of Alzheimer beta-amyloid precursor protein and the signaling receptor Notch is mediated by the presenilin (PS, PS1/PS2)-gamma-secretase complex, the components of which also include nicastrin, APH-1, and PEN-2. In addition to its essential role in gamma-secretase activity, we and others have reported that PS1 plays a role in intracellular trafficking of select membrane proteins including nicastrin. Here we examined the fate of PEN-2 in the absence of PS expression or gamma-secretase activity. We found that PEN-2 is retained in the endoplasmic reticulum and has a much shorter half-life in PS-deficient cells than in wild type cells, suggesting that PSs are required for maintaining the stability and proper subcellular trafficking of PEN-2. However, the function of PS in PEN-2 trafficking is distinct from its contribution to gamma-secretase activity because inhibition of gamma-secretase activity by gamma-secretase inhibitors did not affect the PEN-2 level or its egress from the endoplasmic reticulum. Instead, membrane-permeable gamma-secretase inhibitors, but not a membrane-impermeable derivative, markedly increased the cell surface levels of PS1 and PEN-2 without affecting that of nicastrin. In suppor...Continue Reading

References

Apr 30, 1996·Proceedings of the National Academy of Sciences of the United States of America·H XuS Gandy
Apr 15, 1997·Proceedings of the National Academy of Sciences of the United States of America·H XuS Gandy
Jun 20, 1998·The Journal of Biological Chemistry·J ZhangE H Koo
Jan 20, 1999·Proceedings of the National Academy of Sciences of the United States of America·J P GreenfieldH Xu
Jun 12, 1999·American Journal of Human Genetics·S S SisodiaG Thinakaran
Dec 14, 1999·The Journal of Biological Chemistry·W J RayA M Goate
Feb 22, 2000·Biological Psychiatry·P H St George-Hyslop
Mar 7, 2000·Frontiers in Bioscience : a Journal and Virtual Library·J P GreenfieldH Xu
Aug 1, 2000·The Journal of Biological Chemistry·D SeiffertR Zaczek
Mar 22, 2001·Journal of Neurochemistry·M S Wolfe
Aug 3, 2001·Nature Cell Biology·F ChenP H St George-Hyslop
Jan 17, 2002·Proceedings of the National Academy of Sciences of the United States of America·Caroline GoutteJames R Priess
Jan 31, 2002·Journal of Molecular Neuroscience : MN·G Thinakaran
Feb 2, 2002·The Journal of Biological Chemistry·Jeffrey P GreenfieldHuaxi Xu
Apr 12, 2002·The Journal of Biological Chemistry·Jae Yoon LeemGopal Thinakaran
Jun 6, 2002·Proceedings of the National Academy of Sciences of the United States of America·Dieter EdbauerHarald Steiner
Jul 20, 2002·The Journal of Biological Chemistry·W Taylor KimberlyDennis J Selkoe

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Citations

Sep 27, 2013·Proceedings of the National Academy of Sciences of the United States of America·Yuan TianPaul Greengard
Mar 4, 2011·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Yuan TianPaul Greengard
Feb 2, 2006·Molecular and Cellular Biology·Ruishan WangZhuohua Zhang
Aug 26, 2006·Molecular Neurodegeneration·Kulandaivelu S VetrivelGopal Thinakaran
Oct 7, 2008·Molecular Neurodegeneration·Károly MirnicsSangram S Sisodia
Nov 26, 2004·Proceedings of the National Academy of Sciences of the United States of America·Leonid TarassishinYue-Ming Li
Feb 2, 2006·Proceedings of the National Academy of Sciences of the United States of America·Dongming CaiPaul Greengard
Aug 25, 2007·Pharmacology & Therapeutics·Mark A Findeis
Jul 31, 2013·European Journal of Pharmacology·Stefano MusardoElena Marcello
Jan 8, 2015·Frontiers in Cellular Neuroscience·Xian ZhangYun-Wu Zhang
Dec 6, 2008·Seminars in Cell & Developmental Biology·Ragna Sannerud, Wim Annaert
Dec 23, 2004·The Journal of Biological Chemistry·Douglas R WoodMagali Kitzmann
Sep 29, 2009·Journal of Neurochemistry·Chie MizumaruToshiharu Suzuki
Feb 25, 2006·Traffic·Marloes RéchardsJudith Klumperman
Nov 24, 2005·The Journal of Biological Chemistry·Andreas KernChristian Behl
Apr 29, 2006·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Ruishan WangHuaxi Xu
Apr 29, 2006·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Mei ZhangDora M Kovacs
Sep 22, 2012·International Journal of Geriatric Psychiatry·Armando PiccinniLiliana Dell'Osso
Aug 26, 2016·Journal of Molecular Neuroscience : MN·M A Greenough
Aug 20, 2011·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Changhwan JangEun-Kyoung Choi
Apr 3, 2007·Neurochemical Research·Zhiping HuTing Li
Jul 26, 2011·Neurobiology of Disease·Eun Ji GongJaewon Lee

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