The Tau Tubulin Kinases TTBK1/2 Promote Accumulation of Pathological TDP-43

Nicole F. Liachko, Pamela J. McMillan, Timothy J. Strovas, Elaine Loomis, Lynne Greenup, Jill R. Murrell, Bernardino Ghetti, Murray A. Raskind, Thomas J. Montine, Thomas D. Bird, James B. Leverenz, Brian C. Kraemer

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

Pathological aggregates of phosphorylated TDP-43 characterize amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP), two devastating groups of neurodegenerative disease. Kinase hyperactivity may be a consistent feature of ALS and FTLD-TDP, as phosphorylated TDP-43 is not observed in the absence of neurodegeneration. By examining changes in TDP-43 phosphorylation state, we have identified kinases controlling TDP-43 phosphorylation in a C. elegans model of ALS. In this kinome-wide survey, we identified homologs of the tau tubulin kinases 1 and 2 (TTBK1 and TTBK2), which were also identified in a prior screen for kinase modifiers of TDP-43 behavioral phenotypes. Using refined methodology, we demonstrate TTBK1 and TTBK2 directly phosphorylate TDP-43 in vitro and promote TDP-43 phosphorylation in mammalian cultured cells. TTBK1/2 overexpression drives phosphorylation and relocalization of TDP-43 from the nucleus to cytoplasmic inclusions reminiscent of neuropathologic changes in disease states. Furthermore, protein levels of TTBK1 and TTBK2 are increased in frontal cortex of FTLD-TDP patients, and TTBK1 and TTBK2 co-localize with TDP-43 inclusions in ALS spinal cord. These kinases may represent attractive targets for therapeutic intervention for TDP-43 proteinopathies such as ALS and FTLD-TDP.

Original languageEnglish (US)
JournalPLoS Genetics
Volume10
Issue number12
DOIs
StatePublished - Dec 1 2014
Externally publishedYes

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

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    Liachko, N. F., McMillan, P. J., Strovas, T. J., Loomis, E., Greenup, L., Murrell, J. R., Ghetti, B., Raskind, M. A., Montine, T. J., Bird, T. D., Leverenz, J. B., & Kraemer, B. C. (2014). The Tau Tubulin Kinases TTBK1/2 Promote Accumulation of Pathological TDP-43. PLoS Genetics, 10(12). https://doi.org/10.1371/journal.pgen.1004803