TIA1 regulates the generation and response to toxic tau oligomers

Lulu Jiang, Peter E.A. Ash, Brandon F. Maziuk, Heather I. Ballance, Samantha Boudeau, Ali Al Abdullatif, Marcello Orlando, Leonard Petrucelli, Tsuneya Ikezu, Benjamin Wolozin

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

RNA binding proteins (RBPs) are strongly linked to the pathophysiology of motor neuron diseases. Recent studies show that RBPs, such as TIA1, also contribute to the pathophysiology of tauopathy. RBPs co-localize with tau pathology, and reduction of TIA1 protects against tau-mediated neurodegeneration. The mechanism through which TIA1 reduction protects against tauopathy, and whether TIA1 modulates the propagation of tau, are unknown. Previous studies indicate that the protective effect of TIA1 depletion correlates with both the reduction of oligomeric tau and the reduction of pathological TIA1 positive tau inclusions. In the current report, we used a novel tau propagation approach to test whether TIA1 is required for producing toxic tau oligomers and whether TIA1 reduction would provide protection against the spread of these oligomers. The approach used young PS19 P301S tau mice at an age at which neurodegeneration would normally not yet occur and seeding oligomeric or fibrillar tau by injection into hippocampal CA1 region. We find that propagation of exogenous tau oligomers (but not fibrils) across the brain drives neurodegeneration in this model. We demonstrate that TIA1 reduction essentially brackets the pathophysiology of tau, being required for the production of tau oligomers, as well as regulating the response of neurons to propagated toxic tau oligomers. These results indicate that RNA binding proteins modulate the pathophysiology of tau at multiple levels and provide insights into possible therapeutic approaches to reduce the spread of neurodegeneration in tauopathy.

Original languageEnglish (US)
JournalActa Neuropathologica
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

RNA-Binding Proteins
Poisons
Tauopathies
Hippocampal CA1 Region
Motor Neuron Disease
Pathology
Neurons
Injections
Brain
Therapeutics

Keywords

  • Neurodegeneration
  • Neuropathology
  • RNA binding proteins
  • Stress granules
  • Tau fibrils
  • Tau oligomers
  • Tau propagation
  • Tauopathy
  • TIA1

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Jiang, L., Ash, P. E. A., Maziuk, B. F., Ballance, H. I., Boudeau, S., Abdullatif, A. A., ... Wolozin, B. (Accepted/In press). TIA1 regulates the generation and response to toxic tau oligomers. Acta Neuropathologica. https://doi.org/10.1007/s00401-018-1937-5

TIA1 regulates the generation and response to toxic tau oligomers. / Jiang, Lulu; Ash, Peter E.A.; Maziuk, Brandon F.; Ballance, Heather I.; Boudeau, Samantha; Abdullatif, Ali Al; Orlando, Marcello; Petrucelli, Leonard; Ikezu, Tsuneya; Wolozin, Benjamin.

In: Acta Neuropathologica, 01.01.2018.

Research output: Contribution to journalArticle

Jiang, L, Ash, PEA, Maziuk, BF, Ballance, HI, Boudeau, S, Abdullatif, AA, Orlando, M, Petrucelli, L, Ikezu, T & Wolozin, B 2018, 'TIA1 regulates the generation and response to toxic tau oligomers', Acta Neuropathologica. https://doi.org/10.1007/s00401-018-1937-5
Jiang L, Ash PEA, Maziuk BF, Ballance HI, Boudeau S, Abdullatif AA et al. TIA1 regulates the generation and response to toxic tau oligomers. Acta Neuropathologica. 2018 Jan 1. https://doi.org/10.1007/s00401-018-1937-5
Jiang, Lulu ; Ash, Peter E.A. ; Maziuk, Brandon F. ; Ballance, Heather I. ; Boudeau, Samantha ; Abdullatif, Ali Al ; Orlando, Marcello ; Petrucelli, Leonard ; Ikezu, Tsuneya ; Wolozin, Benjamin. / TIA1 regulates the generation and response to toxic tau oligomers. In: Acta Neuropathologica. 2018.
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