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.
Subject(s)
Calcium/metabolism , Cell Nucleus/metabolism , tau Proteins/metabolism , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Animals , Animals, Genetically Modified , Brain/metabolism , Cyclic AMP Response Element-Binding Protein/metabolism , Drosophila melanogaster/genetics , Drosophila melanogaster/metabolism , Gene Expression Profiling , Gene Expression Regulation , Induced Pluripotent Stem Cells/metabolism , Membrane Potentials , Neurons/metabolism , Neurotoxins/toxicityABSTRACT
Nearly half (45%) of the human genome is composed of transposable elements, or 'jumping genes'. Since Barbara McClintock's original discovery of transposable elements in 1950, we have come to appreciate that transposable element mobilization is a major driver of evolution that transposons are active in the germline and the soma, and that transposable element dysregulation is causally associated with many human disorders. In the present review, we highlight recent studies investigating transposable element activation in the adult brain and in the context of neurodegeneration. Collectively, these studies contribute to a greater understanding of the frequency of complete retrotransposition in the adult brain as well as the presence of transposable element-derived RNA and protein in brain and fluids of patients with neurodegenerative disorders. We discuss therapeutic opportunities and speculate on the larger implications of transposable element activation in regard to current hot topics in the field of neurodegeneration.
