Pathogenic Tau Causes a Toxic Depletion of Nuclear Calcium
Rebekah Mahoney,
Elizabeth Ochoa Thomas,
Paulino Ramirez,
Henry E. Miller,
Adrian Beckmann,
Gabrielle Zuniga,
Radek Dobrowolski,
Bess Frost
Affiliations
Rebekah Mahoney
Barshop Institute for Longevity and Aging Studies, University of Texas Health, San Antonio, San Antonio, TX, USA; Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health, San Antonio, San Antonio, TX, USA; Department of Cell Systems and Anatomy, University of Texas Health, San Antonio, San Antonio, TX, USA
Elizabeth Ochoa Thomas
Barshop Institute for Longevity and Aging Studies, University of Texas Health, San Antonio, San Antonio, TX, USA; Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health, San Antonio, San Antonio, TX, USA; Department of Cell Systems and Anatomy, University of Texas Health, San Antonio, San Antonio, TX, USA
Paulino Ramirez
Barshop Institute for Longevity and Aging Studies, University of Texas Health, San Antonio, San Antonio, TX, USA; Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health, San Antonio, San Antonio, TX, USA; Department of Cell Systems and Anatomy, University of Texas Health, San Antonio, San Antonio, TX, USA
Henry E. Miller
Department of Cell Systems and Anatomy, University of Texas Health, San Antonio, San Antonio, TX, USA; Greehey Children’s Cancer Institute, University of Texas Health, San Antonio, San Antonio, TX, USA
Adrian Beckmann
Barshop Institute for Longevity and Aging Studies, University of Texas Health, San Antonio, San Antonio, TX, USA; Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health, San Antonio, San Antonio, TX, USA; Department of Cell Systems and Anatomy, University of Texas Health, San Antonio, San Antonio, TX, USA
Gabrielle Zuniga
Barshop Institute for Longevity and Aging Studies, University of Texas Health, San Antonio, San Antonio, TX, USA; Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health, San Antonio, San Antonio, TX, USA; Department of Cell Systems and Anatomy, University of Texas Health, San Antonio, San Antonio, TX, USA
Radek Dobrowolski
Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health, San Antonio, San Antonio, TX, USA; Rutgers University, Newark, NJ, USA
Bess Frost
Barshop Institute for Longevity and Aging Studies, University of Texas Health, San Antonio, San Antonio, TX, USA; Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health, San Antonio, San Antonio, TX, USA; Department of Cell Systems and Anatomy, University of Texas Health, San Antonio, San Antonio, TX, USA; Corresponding author
Summary: 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.
