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.
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Funding: B.W.: NIH ES020395, AG050471, NS089544 (B.W./L.P.), Alzheimer Association, BrightFocus Foundation, CurePSP Foundation, and the CureAlzheimer Foundation, L.P.: ES20395, AG16574-17JP2, and NS089544, H.L.: NIH CA196631, J.F.A.: NIH NS091329, MD009205, DOD 11811993; T.V.: NIH AG042213.
The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE (Vizcaino et al., 2014) partner repository with the dataset identifier PXD003922 and http://dx.doi.org/10.6019/PXD003922.
Vanderweyde, Tara; Apicco, Daniel J.; Youmans-Kidder, Katherine; Ash, Peter E. A.; Cook, Casey; Lummertz da Rocha, Edroaldo; Jansen-West, Karen; Frame, Alissa A.; Citro, Allison; Leszyk, John D.; Ivanov, Pavel; Abisambra, Jose F.; Steffen, Martin; Li, Hu; Petrucelli, Leonard; and Wolozin, Benjamin, "Interaction of tau with the RNA-Binding Protein TIA1 Regulates tau Pathophysiology and Toxicity" (2016). Sanders-Brown Center on Aging Faculty Publications. 65.