Pathological phosphorylation of tau and TDP-43 by TTBK1 and TTBK2 drives neurodegeneration

Laura M. Taylor, Pamela J. McMillan, Nicole F. Liachko, Timothy J. Strovas, Bernardino Ghetti, Thomas D. Bird, C. Dirk Keene, Brian C. Kraemer

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8 Scopus citations

Abstract

Background: Progressive neuron loss in the frontal and temporal lobes of the cerebral cortex typifies frontotemporal lobar degeneration (FTLD). FTLD sub types are classified on the basis of neuronal aggregated protein deposits, typically containing either aberrantly phosphorylated TDP-43 or tau. Our recent work demonstrated that tau tubulin kinases 1 and 2 (TTBK1/2) robustly phosphorylate TDP-43 and co-localize with phosphorylated TDP-43 in human postmortem neurons from FTLD patients. Both TTBK1 and TTBK2 were initially identified as tau kinases and TTBK1 has been shown to phosphorylate tau epitopes commonly observed in Alzheimer's disease and other tauopathies. Methods: To further elucidate how TTBK1/2 activity contributes to both TDP-43 and tau phosphorylation in the context of the neurodegeneration seen in FTLD, we examined the consequences of elevated human TTBK1/2 kinase expression in transgenic animal models of disease. Results: We show that C. elegans co-expressing tau/TTBK1 tau/TTBK2, or TDP-43/TTBK1 transgenes in combination exhibit synergistic exacerbation of behavioral abnormalities and increased pathological protein phosphorylation. We also show that C. elegans co-expressing tau/TTBK1 or tau/TTBK2 transgenes in combination exhibit aberrant neuronal architecture and neuron loss. Surprisingly, the TTBK2/TDP-43 transgenic combination showed no exacerbation of TDP-43 proteinopathy related phenotypes. Additionally, we observed elevated TTBK1/2 protein expression in cortical and hippocampal neurons of FTLD-tau and FTLD-TDP cases relative to normal controls. Conclusions: Our findings suggest a possible etiology for the two most common FTLD subtypes through a kinase activation driven mechanism of neurodegeneration.

Original languageEnglish (US)
Article number7
JournalMolecular Neurodegeneration
Volume13
Issue number1
DOIs
StatePublished - Feb 6 2018

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Keywords

  • C. elegans
  • Frontotemporal lobar degeneration
  • Neurodegeneration
  • TDP-43
  • TTBK1
  • TTBK2
  • Tau

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Taylor, L. M., McMillan, P. J., Liachko, N. F., Strovas, T. J., Ghetti, B., Bird, T. D., Dirk Keene, C., & Kraemer, B. C. (2018). Pathological phosphorylation of tau and TDP-43 by TTBK1 and TTBK2 drives neurodegeneration. Molecular Neurodegeneration, 13(1), [7]. https://doi.org/10.1186/s13024-018-0237-9