@article{fb21a296e07e4982b5d22f7b01385739,
title = "Pathogenic Tau Causes a Toxic Depletion of Nuclear Calcium",
abstract = "Synaptic activity-induced calcium (Ca2+) influx and subsequent propagation into the nucleus is a major way in which synapses communicate with the nucleus to regulate transcriptional programs important for activity-dependent survival and memory formation. Nuclear Ca2+ shapes the transcriptome by regulating cyclic AMP (cAMP) response element-binding protein (CREB). Here, we utilize a Drosophila model of tauopathy and induced pluripotent stem cell (iPSC)-derived neurons from humans with Alzheimer's disease to study the effects of pathogenic tau, a pathological hallmark of Alzheimer's disease and related tauopathies, on nuclear Ca2+. We find that pathogenic tau depletes nuclear Ca2+ and CREB to drive neuronal death, that CREB-regulated genes are over-represented among differentially expressed genes in tau transgenic Drosophila, and that activation of big potassium (BK) channels elevates nuclear Ca2+ and suppresses tau-induced neurotoxicity. Our studies identify nuclear Ca2+ depletion as a mechanism contributing to tau-induced neurotoxicity, adding an important dimension to the calcium hypothesis of Alzheimer's disease.",
keywords = "Alzheimer's disease, BK channels, CREB, Drosophila, calcium, iPSC-derived neurons, neurodegeneration, nucleus, tau, tauopathy",
author = "Rebekah Mahoney and {Ochoa Thomas}, Elizabeth and Paulino Ramirez and Miller, {Henry E.} and Adrian Beckmann and Gabrielle Zuniga and Radek Dobrowolski and Bess Frost",
note = "Funding Information: We thank Dr. Hilmar Bading for providing GCaMP3.NLS and UAS-CaMBP4 Drosophila lines and GCaMP6s.NLS constructs and Peter Ngam (NuGen/Tecan) for training in use of the Ovation RNA-Seq system. The UT Health San Antonio Genome Sequencing Facility is supported by UT Health San Antonio, NIH-NCI P30 CA054174 (Cancer Center at UT Health San Antonio), NIH Shared Instrument grant 1S10OD021805 (S10 grant), and CPRIT Core Facility Award (RP160732). The Actin and GFP antibodies were obtained from the Developmental Studies Hybridoma Bank, created by the NICHD of the NIH and maintained at The University of Iowa, Department of Biology, Iowa City, IA 52242. The graphical abstract was created using Adobe Illustrator and Biorender (https://www.biorender.com). This study was supported by the American Federation for Aging Research New Investigator in Alzheimer's Disease (B.F.) and the National Institute on Aging (R01 AG062475 to R.D. and B.F.). R.M. was supported by an NIGMS-funded K12 GM111726. Conceptualization, B.F. R.M. and R.D.; Methodology, R.M. R.D. P.R. and H.E.M.; Formal Analysis, R.M. E.O.T. R.D. P.R. and H.E.M.; Investigation, R.M. E.O.T. R.D. and P.R.; Writing, B.F. E.O.T. R.D. G.Z. and R.M.; Visualization, R.M. E.O.T. R.D. and B.F.; Supervision, B.F.; Funding Acquisition, B.F. R.D. and R.M. The authors declare no competing interests. Funding Information: We thank Dr. Hilmar Bading for providing GCaMP3.NLS and UAS-CaMBP4 Drosophila lines and GCaMP6s.NLS constructs and Peter Ngam (NuGen/Tecan) for training in use of the Ovation RNA-Seq system. The UT Health San Antonio Genome Sequencing Facility is supported by UT Health San Antonio , NIH-NCI P30 CA054174 (Cancer Center at UT Health San Antonio), NIH Shared Instrument grant 1S10OD021805 (S10 grant), and CPRIT Core Facility Award ( RP160732 ). The Actin and GFP antibodies were obtained from the Developmental Studies Hybridoma Bank, created by the NICHD of the NIH and maintained at The University of Iowa, Department of Biology, Iowa City, IA 52242. The graphical abstract was created using Adobe Illustrator and Biorender ( https://www.biorender.com ). This study was supported by the American Federation for Aging Research New Investigator in Alzheimer{\textquoteright}s Disease (B.F.) and the National Institute on Aging ( R01 AG062475 to R.D. and B.F.). R.M. was supported by an NIGMS -funded K12 GM111726 . Publisher Copyright: {\textcopyright} 2020 The Author(s) Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",
year = "2020",
month = jul,
day = "14",
doi = "10.1016/j.celrep.2020.107900",
language = "English (US)",
volume = "32",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "2",
}