Familial Alzheimer's disease mutations in presenilins: effects on endoplasmic reticulum calcium homeostasis and correlation with clinical phenotypes.

Journal of Alzheimer's Disease : JAD
Omar NelsonIlya Bezprozvanny

Abstract

Mutations in presenilins 1 and 2 (PS1 and PS2) are responsible for approximately 40% of all early onset familial Alzheimer's disease (FAD) monogenic cases. Presenilins (PSs) function as the catalytic subunit of γ-secretase and support cleavage of the amyloid-β protein precursor (AβPP). We previously discovered that PSs also function as passive endoplasmic reticulum (ER) calcium (Ca2+) leak channels and that most FAD mutations in PSs affected their ER Ca2+ leak function. To further validate the relevance of our findings to human disease, we here performed Ca2+ imaging experiments with lymphoblasts established from FAD patients. We discovered that most FAD mutations in PSs disrupted ER Ca2+ leak function and resulted in increased ER Ca2+ pool in human lymphoblasts. However, we found that a subset of PS1 FAD mutants supported ER Ca2+ leak activity, as ER Ca2+ pool was unaffected in lymphoblasts. Most of the "functional" mutations for ER Ca2+ leak were clustered in the exon 8-9 area of PSEN1 gene and segregated with the cotton wool plaques and spastic paraparesis clinical phenotype occasionally observed in PS1 FAD patients. Our findings with the "functional" and "non-functional" PS1 FAD mutants were confirmed in Ca2+ rescue experim...Continue Reading

Citations

May 3, 2011·The Journal of Biological Chemistry·Omar NelsonIlya Bezprozvanny
Feb 9, 2012·The Journal of Biological Chemistry·Dustin ShillingJ Kevin Foskett
Jul 9, 2011·Pharmacological Reviews·Grace E Stutzmann, Mark P Mattson
Jul 9, 2013·Molecular Neurodegeneration·Ilya Bezprozvanny, Peter Robin Hiesinger
Jun 25, 2010·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Hua ZhangIlya Bezprozvanny
Jun 7, 2014·Molecular Neurodegeneration·Dolores Del PreteMounia Chami
Apr 22, 2014·Metabolic Brain Disease·Hsueh-Meei HuangGary E Gibson
Jun 13, 2018·Antioxidants & Redox Signaling·Elena PopugaevaIlya Bezprozvanny
Jul 11, 2013·Science Signaling·Ilya Bezprozvanny
Feb 27, 2014·The Journal of Clinical Investigation·Diego Sepulveda-FallaMarkus Glatzel
Oct 14, 2014·Neurological Research·Han-Chang HuangZhao-Feng Jiang
Jul 11, 2012·The Journal of Cell Biology·Ilya Bezprozvanny
Jan 30, 2020·International Journal of Molecular Sciences·Luisa GallaElisa Greotti
Mar 19, 2020·International Journal of Molecular Sciences·Alessandro RabbitoBarbara Mroczko
Mar 9, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Xingjian Wang, Wei Zheng
May 30, 2020·Current Alzheimer Research·Elena PopugaevaIlya Bezprozvanny
Jul 26, 2011·Science China. Life Sciences·Charlene Supnet, Ilya Bezprozvanny
Feb 6, 2013·Journal of Cellular and Molecular Medicine·Kamran HonarnejadJochen Herms
Mar 15, 2016·Protein Science : a Publication of the Protein Society·Douglas L Theobald
Dec 25, 2010·Neurochemical Research·Michael J Berridge
Mar 9, 2021·Trends in Cell Biology·Jens LonckeGeert Bultynck
Apr 9, 2021·Alzheimer's & Dementia : the Journal of the Alzheimer's Association·Dibyadeep DattaAmy F T Arnsten
Aug 17, 2021·Cell Calcium·Dmitry LimAlexei Verkhratsky
May 19, 2020·The Journal of Physical Chemistry. B·Rukmankesh Mehra, Kasper P Kepp

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