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

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

Author information

1
Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA.
2
Department of Anatomy, Boston University School of Medicine, Boston, MA, USA.
3
Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
4
Department of Environmental Health, Boston University School of Public Health, Boston, MA, USA.
5
Department of Translational Science and Molecular Medicine, College of Human Medicine, Michigan State University, East Lansing, MI, USA.
6
Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
7
Department of Biochemistry and Molecular Pathology, University of Massachusetts Medical Center, Worcester, MA, USA.
8
Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA. bwolozin@bu.edu.
9
Department of Neurology, Boston University School of Medicine, Boston, MA, USA. bwolozin@bu.edu.

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.

Comment in

PMID:
29273772
PMCID:
PMC5745051
DOI:
10.1038/s41593-017-0022-z
[Indexed for MEDLINE]
Free PMC Article

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