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, Wolozin Benjamin
Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA.
Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Cell Rep. 2016 May 17;15(7):1455-1466. doi: 10.1016/j.celrep.2016.04.045. Epub 2016 May 6.
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.
微管相关蛋白tau在树突中的错误定位是tau蛋白病的一个标志，但树突中tau的作用尚不清楚。我们现在报告tau在脑组织中与RNA结合蛋白（RBP）TIA1相互作用，并且我们展示了TIA1的脑蛋白相互作用组网络。对野生型（WT）和tau基因敲除小鼠脑组织中TIA1相互作用组的分析表明，tau是TIA1与参与RNA代谢的蛋白质（包括核糖体蛋白和RBPs）正常相互作用所必需的。表达研究表明，tau调节TIA1的分布，并且tau加速应激颗粒（SG）的形成。相反，TIA1的敲低或敲除抑制了培养的海马神经元中tau的错误折叠及相关毒性，而TIA1的过表达则诱导tau的错误折叠并刺激神经退行性变。防止SG形成的药理学干预也抑制了tau的病理生理学。这些研究表明，tau蛋白病的病理生理学需要与RNA结合蛋白密切相互作用。
