Interaction of tau with the RNA-Binding Protein TIA1 Regulates tau Pathophysiology and Toxicity

Tara Vanderweyde, Daniel J. Apicco, Katherine Youmans-Kidder, Peter E.A. Ash, Casey Cook, Edroaldo Lummertz da Rocha, Karen Jansen-West, Alissa A. Frame, Allison Citro, John D. Leszyk, Pavel Ivanov, Jose F. Abisambra, Martin Steffen, Hu Li, Leonard Petrucelli, Benjamin Wolozin

Research output: Contribution to journalArticle

105 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1455-1466
Number of pages12
JournalCell reports
Volume15
Issue number7
DOIs
StatePublished - May 17 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Vanderweyde, T., Apicco, D. J., Youmans-Kidder, K., Ash, P. E. A., Cook, C., Lummertz da Rocha, E., Jansen-West, K., Frame, A. A., Citro, A., Leszyk, J. D., Ivanov, P., Abisambra, J. F., Steffen, M., Li, H., Petrucelli, L., & Wolozin, B. (2016). Interaction of tau with the RNA-Binding Protein TIA1 Regulates tau Pathophysiology and Toxicity. Cell reports, 15(7), 1455-1466. https://doi.org/10.1016/j.celrep.2016.04.045