Reducing the RNA binding protein TIA1 protects against tau-mediated neurodegeneration in vivo

Emerging studies suggest a role for tau in regulating the biology of RNA binding proteins (RBPs). We now show that reducing the RBP T-cell intracellular antigen 1 (TIA1) in vivo protects against neurodegeneration and prolongs survival in transgenic P301S Tau mice. Biochemical fractionation shows co-...

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Published in:	Nature neuroscience Vol. 21; no. 1; pp. 72 - 80
Main Authors:	Apicco, Daniel J., Ash, Peter E. A., Maziuk, Brandon, LeBlang, Chelsey, Medalla, Maria, Al Abdullatif, Ali, Ferragud, Antonio, Botelho, Emily, Ballance, Heather I., Dhawan, Uma, Boudeau, Samantha, Cruz, Anna Lourdes, Kashy, Daniel, Wong, Aria, Goldberg, Lisa R., Yazdani, Neema, Zhang, Cheng, Ung, Choong Y., Tripodis, Yorghos, Kanaan, Nicholas M., Ikezu, Tsuneya, Cottone, Pietro, Leszyk, John, Li, Hu, Luebke, Jennifer, Bryant, Camron D., Wolozin, Benjamin
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01-01-2018 Nature Publishing Group
Subjects:	631/378/1689 692/699/375/132/1283 Analysis Animal Genetics and Genomics Animals Animals, Newborn Antigens Behavioral Sciences Binding proteins Biochemistry Biocompatibility Biological Techniques Biomedical and Life Sciences Biomedicine Cognition Disorders - etiology Cognition Disorders - genetics Cytoplasm - metabolism Cytoplasm - pathology Cytoplasm - ultrastructure Disease Models, Animal Endoribonucleases - metabolism Female Fractionation Gene Expression Regulation - genetics Genetic engineering Granular materials In vivo methods and tests Life span Localization Locomotion - genetics Lymphocytes T Male Maze Learning - physiology Medical research Mice Mice, Inbred C57BL Mice, Transgenic Mutation - genetics Neurobiology Neurodegeneration Neurodegenerative diseases Neurofibrillary tangles Neurofibrillary Tangles - metabolism Neurofibrillary Tangles - pathology Neurofibrillary Tangles - ultrastructure Neurons Neurons - pathology Neurons - ultrastructure Neurosciences Oligomers Pathological physiology Protein binding Proteins Ribonucleic acid RNA RNA-binding protein RNA-Binding Proteins - genetics RNA-Binding Proteins - metabolism Survival Synapses - metabolism Synapses - ultrastructure T cells Tau protein tau Proteins - genetics tau Proteins - metabolism Tauopathies - genetics Tauopathies - metabolism Tauopathies - pathology Tauopathies - prevention & control TIA-1 protein Toxicity Trans-Activators - metabolism Transgenic mice
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Summary:	Emerging studies suggest a role for tau in regulating the biology of RNA binding proteins (RBPs). We now show that reducing the RBP T-cell intracellular antigen 1 (TIA1) in vivo protects against neurodegeneration and prolongs survival in transgenic P301S Tau mice. Biochemical fractionation shows co-enrichment and co-localization of tau oligomers and RBPs in transgenic P301S Tau mice. Reducing TIA1 decreased the number and size of granules co-localizing with stress granule markers. Decreasing TIA1 also inhibited the accumulation of tau oligomers at the expense of increasing neurofibrillary tangles. Despite the increase in neurofibrillary tangles, TIA1 reduction increased neuronal survival and rescued behavioral deficits and lifespan. These data provide in vivo evidence that TIA1 plays a key role in mediating toxicity and further suggest that RBPs direct the pathway of tau aggregation and the resulting neurodegeneration. We propose a model in which dysfunction of the translational stress response leads to tau-mediated pathology. Apicco and colleagues show that reducing TIA1 inhibits tau-mediated neurodegeneration and improves survival in a mouse model of tauopathy. This rescue occurs with a transition in tau aggregation from oligomeric to fibrillar forms of tau. These findings suggest a key role for RNA binding proteins in the pathophysiology of tau.
ISSN:	1097-6256 1546-1726
DOI:	10.1038/s41593-017-0022-z