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

Nat Neurosci. 2018 Jan;21(1):72-80. doi: 10.1038/s41593-017-0022-z. Epub 2017 Nov 20.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Cognition Disorders / etiology
  • Cognition Disorders / genetics
  • Cytoplasm / metabolism
  • Cytoplasm / pathology
  • Cytoplasm / ultrastructure
  • Disease Models, Animal
  • Endoribonucleases / metabolism
  • Female
  • Gene Expression Regulation / genetics*
  • Locomotion / genetics
  • Male
  • Maze Learning / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation / genetics
  • Neurofibrillary Tangles / metabolism
  • Neurofibrillary Tangles / pathology
  • Neurofibrillary Tangles / ultrastructure
  • Neurons / pathology
  • Neurons / ultrastructure
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Synapses / metabolism
  • Synapses / ultrastructure
  • Tauopathies / genetics
  • Tauopathies / metabolism*
  • Tauopathies / pathology
  • Tauopathies / prevention & control*
  • Trans-Activators / metabolism
  • tau Proteins / genetics
  • tau Proteins / metabolism*

Substances

  • RNA-Binding Proteins
  • Tial1 protein, mouse
  • Trans-Activators
  • tau Proteins
  • Endoribonucleases
  • smad4-interacting protein SMIF, mouse