Presenilin proteins undergo heterogeneous endoproteolysis between Thr291 and Ala299 and occur as stable N- and C-terminal fragments in normal and Alzheimer brain tissue

Neurobiology of Disease
M B PodlisnyD J Selkoe

Abstract

Humans inheriting missense mutations in the presenilin (PS)1 and -2 genes undergo progressive cerebral deposition of the amyloid beta-protein at an early age and develop a clinically and pathologically severe form of familial Alzheimer's disease (FAD). Because PS1 mutations cause the most aggressive known form of AD, it is important to elucidate the structure and function of this multitransmembrane protein in the brain. Using a panel of region-specific PS antibodies, we characterized the presenilin polypeptides in mammalian tissues, including brains of normal, AD, and PS1-linked FAD subjects, and in transfected and nontransfected cell lines. Very little full-length PS1 or -2 was detected in brain and untransfected cells; instead the protein occurred as a heterogeneous array of stable N- and C-terminal proteolytic fragments that differed subtly among cell types and mammalian tissues. Sequencing of the major C-terminal fragment from PS1-transfected human 293 cells showed that the principal endoproteolytic cleavage occurs at and near Met298 in the proximal portion of the large hydrophilic loop. Full-length PS1 in these cells is quickly turned over (T1/2 approximately 60 min), in part to the two major fragments. The sizes and amoun...Continue Reading

Citations

Sep 1, 2006·Neurochemical Research·Giuseppe VerdileRalph N Martins
Jun 20, 2012·Biochemistry·Kathleen F MittendorfCharles R Sanders
Feb 20, 2009·Chemical Reviews·Michael S Wolfe
Jun 11, 1999·Clinical Genetics·M NishimuraP H St George-Hyslop
Feb 20, 2002·European Journal of Clinical Investigation·J V R B HendriksenH A Smits
Oct 3, 2008·The Journal of Biological Chemistry·Toru SatoMichael S Wolfe
Sep 26, 2000·Human Molecular Genetics·H Tanahashi, T Tabira
Jun 18, 2002·Journal of Cellular and Molecular Medicine·B. O. Popescu, Maria Ankarcrona
Feb 27, 2008·Molecular and Cellular Biology·María-Ximena SilveyraJavier Sáez-Valero
Feb 3, 1999·Annual Review of Genetics·D L PriceS S Sisodia
Jul 27, 2002·Annual Review of Genomics and Human Genetics·Dennis J Selkoe, Marcia B Podlisny
Apr 8, 1998·Annual Review of Neuroscience·D L Price, S S Sisodia
May 6, 2003·Annual Review of Neuroscience·Dennis Selkoe, Raphael Kopan
Apr 22, 2005·American Journal of Physiology. Cell Physiology·Young S Oh, R James Turner
Aug 16, 2006·Neuro-degenerative Diseases·Loukia ParisiadouSpiros Efthimiopoulos
Nov 24, 1999·The Journal of Clinical Investigation·G Thinakaran
Aug 26, 2006·Molecular Neurodegeneration·Kulandaivelu S VetrivelGopal Thinakaran
Jul 23, 2013·Translational Neurodegeneration·Shuting ZhangWeihong Song
Nov 21, 2013·Acta Neuropathologica Communications·María-Salud García-AyllónJavier Sáez-Valero
Jun 23, 2012·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Xulun ZhangSangram S Sisodia
Mar 4, 2000·Proceedings of the National Academy of Sciences of the United States of America·X LinJ Tang
Oct 21, 2003·Proceedings of the National Academy of Sciences of the United States of America·Eric H SchroeterRaphael Kopan
Feb 12, 1998·Proceedings of the National Academy of Sciences of the United States of America·N N Dewji, S J Singer
Mar 17, 1999·Proceedings of the National Academy of Sciences of the United States of America·W J RayA M Goate
Sep 27, 2001·Proceedings of the National Academy of Sciences of the United States of America·D J Selkoe
Feb 28, 2002·Proceedings of the National Academy of Sciences of the United States of America·William P EslerMichael S Wolfe
Sep 2, 1997·Proceedings of the National Academy of Sciences of the United States of America·N N Dewji, S J Singer
Feb 28, 2001·Proceedings of the National Academy of Sciences of the United States of America·L BakiN K Robakis
Mar 14, 2003·Proceedings of the National Academy of Sciences of the United States of America·Wesley FarrisSuzanne Guenette
Jul 22, 1997·Proceedings of the National Academy of Sciences of the United States of America·W XiaD J Selkoe
May 17, 2000·Proceedings of the National Academy of Sciences of the United States of America·L KulicC Haass
Aug 2, 2000·Proceedings of the National Academy of Sciences of the United States of America·W XiaD J Selkoe
May 2, 2001·The Journal of Cell Biology·J W KimE J Choi
Apr 29, 2005·Journal of Neurochemistry·A L Brunkan, A M Goate
Dec 1, 2004·Annual Review of Genetics·Michael Ehrmann, Tim Clausen
Jan 8, 2015·Frontiers in Cellular Neuroscience·Xian ZhangYun-Wu Zhang
Jan 23, 2015·Frontiers in Aging Neuroscience·Natalya GertsikYue-Ming Li
Mar 25, 2016·FEBS Letters·Khoa Pham, Jaroslava Miksovska
Mar 18, 2005·Comptes rendus biologies·Peter H St George-Hyslop, Agnès Petit
May 17, 2005·Brain Research. Molecular Brain Research·Annamaria ConfaloniGianluigi Forloni

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