title: Interaction of tau with the RNA-Binding Protein TIA1 Regulates tau Pathophysiology and Toxicity.
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.
authors.affiliation: Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Tara
authors.initials: T
authors.lastname: Vanderweyde
authors.affiliation: Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Apicco
authors.affiliation: Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Youmans-Kidder
authors.affiliation: Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Peter E A
authors.initials: PEA
authors.lastname: Ash
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
authors.forename: Casey
authors.initials: C
authors.lastname: Cook
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Edroaldo
authors.initials: E
authors.lastname: Lummertz da Rocha
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Jansen-West
authors.affiliation: Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Alissa A
authors.initials: AA
authors.lastname: Frame
authors.affiliation: Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Citro
authors.affiliation: Department of Biochemistry and Molecular Pathology, University of Massachusetts Medical School, Shrewsbury, MA 01545, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Leszyk
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Pavel
authors.initials: P
authors.lastname: Ivanov
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506, USA.
authors.forename: Jose F
authors.initials: JF
authors.lastname: Abisambra
authors.affiliation: Department of Pathology and Laboratory Medicine, Boston University, Boston, MA 02118, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Steffen
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Hu
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
authors.forename: Leonard
authors.initials: L
authors.lastname: Petrucelli
authors.affiliation: Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA; Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA. Electronic address: bwolozin@bu.edu.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wolozin
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000378:metabolism; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D011485:Protein Binding / Q000187:drug effects; D017510:Protein Folding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D055550:Protein Stability / Q000187:drug effects; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D020543:Proteome / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D012995:Solubility; D000074019:T-Cell Intracellular Antigen-1; D024801:Tauopathies / Q000378:metabolism* / Q000503:physiopathology*; D016875:tau Proteins / Q000378:metabolism* / Q000633:toxicity*
chemical_list: D047428:Protein Kinase Inhibitors; D011500:Protein Synthesis Inhibitors; D020543:Proteome; D016601:RNA-Binding Proteins; D000074019:T-Cell Intracellular Antigen-1; C499367:Tia1 protein, mouse; D016875:tau Proteins