Pathogenic Tau Causes a Toxic Depletion of Nuclear Calcium.

Cell Reports
Rebekah MahoneyBess Frost

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.

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Citations

Nov 9, 2020·Trends in Neurosciences·Maria Calvo-Rodriguez, Brian J Bacskai
Jan 10, 2021·Life·Grazyna NiewiadomskaAnna Gasiorowska
Apr 30, 2021·Journal of Cell Science·Pawel MozolewskiRadek Dobrowolski
Aug 28, 2021·Cells·Nelly RedolfiDiana Pendin

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Datasets Mentioned

BETA
GSE152278
GSM1892406
and
GSM1892408

Methods Mentioned

BETA
transgenic
immunoprecipitation
RNA-seq
Genome Sequencing
ChIP-seq
dissection
transfection
confocal microscopy

Software Mentioned

Qubit
FindM
Trimmomatic
ChIPpeakAnno
FastQC
DESeq2
Salmon
ImageJ
GO Enrichment Analysis

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