1. Interaction of tau with the RNA-Binding Protein TIA1 Regulates tau Pathophysiology and Toxicity
- Author
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Benjamin Wolozin, Pavel Ivanov, Allison Citro, Hu Li, Alissa A. Frame, Leonard Petrucelli, Martin Steffen, Tara Vanderweyde, Jose F. Abisambra, Casey Cook, Daniel J. Apicco, Karen Jansen-West, Edroaldo Lummertz da Rocha, Peter E.A. Ash, John D. Leszyk, and Katherine Youmans-Kidder
- Subjects
0301 basic medicine ,Protein Folding ,TIA1 ,Proteome ,tau Proteins ,RNA-binding protein ,Biology ,Cytoplasmic Granules ,Interactome ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Stress granule ,mental disorders ,medicine ,Animals ,Protein Kinase Inhibitors ,lcsh:QH301-705.5 ,Protein Synthesis Inhibitors ,Gene knockdown ,Protein Stability ,Neurodegeneration ,Brain ,RNA-Binding Proteins ,Dendrites ,medicine.disease ,T-Cell Intracellular Antigen-1 ,Cell biology ,Transport protein ,Mice, Inbred C57BL ,Protein Transport ,030104 developmental biology ,Solubility ,Tauopathies ,lcsh:Biology (General) ,Tauopathy ,Protein Binding - Abstract
Summary: Dendritic mislocalization of microtubule associated protein tau is a hallmark of tauopathies, but the role of dendritic tau is unknown. We now report that tau interacts with the RNA-binding protein (RBP) TIA1 in brain tissue, and we present the brain-protein interactome network for TIA1. Analysis of the TIA1 interactome in brain tissue from wild-type (WT) and tau knockout mice demonstrates that tau is required for normal interactions of TIA1 with proteins linked to RNA metabolism, including ribosomal proteins and RBPs. Expression studies show that tau regulates the distribution of TIA1, and tau accelerates stress granule (SG) formation. Conversely, TIA1 knockdown or knockout inhibits tau misfolding and associated toxicity in cultured hippocampal neurons, while overexpressing TIA1 induces tau misfolding and stimulates neurodegeneration. Pharmacological interventions that prevent SG formation also inhibit tau pathophysiology. These studies suggest that the pathophysiology of tauopathy requires an intimate interaction with RNA-binding proteins. : Vanderweyde et al. show that the interaction of microtubule associated protein tau with the RNA binding protein (RBP) TIA1 regulates stress granule (SG) formation as well as misfolding and aggregation of tau. TIA1 knockdown prevents tau misfolding and tau-mediated toxicity, which points to RBPs as potential targets for therapy of tauopathies.
- Published
- 2016