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

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

doi:10.1016/j.celrep.2016.04.045

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.

Highlights

RNA-binding proteins (RBPs) are a class of about 800 proteins that function in the nucleus to regulate mRNA maturation, including splicing, RNA helicase activity, RNA polymerase elongation, and nuclear export (Anderson and Kedersha, 2008)
Reducing T cell intracellular antigen 1 (TIA1) inhibits tau-misfolding and degeneration in neuronal cultures. These results indicate that tau plays an important role in neuronal RBP biology and suggest that RBPs and stress granule (SG) contribute to the misfolding of tau
Tau Increases Somatodendritic Localization of TIA1 The distribution of TIA1 was examined in primary cultures of hippocampal neurons from wild-type (WT) and tauÀ/À mice to investigate whether tau regulates the distribution of TIA1 (Figure 1A)

Summary

Introduction

RNA-binding proteins (RBPs) are a class of about 800 proteins that function in the nucleus to regulate mRNA maturation, including splicing, RNA helicase activity, RNA polymerase elongation, and nuclear export (Anderson and Kedersha, 2008). RBPs function in the cytoplasm where they regulate RNA translation, trafficking, sequestration, and degradation. RBP function is strongly regulated by the multiple signaling cascades integrated with RNA translation/protein synthesis, which will be referred to as ‘‘translational signaling.’’ The cytoplasmic actions of RBPs play a crucial role in neurobiology because the large distance between the soma and synapse demands a proportionately large role of RBPs in the trafficking of mRNA transcripts (Liu-Yesucevitz et al, 2011). Nucleation by core RBPs, such as TIA1, is followed by recruitment of secondary RBPs to form a mature SG, which is a key component of stress-induced translational suppression. SGs play a dynamic role in mRNA triage by sorting sequestered mRNAs for re-initiation, storage, or degradation

Results

Discussion

Conclusion