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.
Original language | English (US) |
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Article number | 107900 |
Journal | Cell Reports |
Volume | 32 |
Issue number | 2 |
DOIs | |
State | Published - Jul 14 2020 |
Keywords
- Alzheimer's disease
- BK channels
- CREB
- Drosophila
- calcium
- iPSC-derived neurons
- neurodegeneration
- nucleus
- tau
- tauopathy
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology