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

30 Citations (Scopus)

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
JournalPLoS Genetics
Volume10
Issue number12
DOIs
StatePublished - Dec 1 2014

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Amyotrophic Lateral Sclerosis
Frontotemporal Dementia
phosphorylation
phosphotransferases (kinases)
Phosphotransferases
Phosphorylation
phenotype
TDP-43 Proteinopathies
protein
methodology
Frontotemporal Lobar Degeneration
cytoplasmic inclusions
Inclusion Bodies
neurodegenerative diseases
Frontal Lobe
cell aggregates
spinal cord
Neurodegenerative Diseases
cultured cells
Cultured Cells

ASJC Scopus subject areas

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

Cite this

Liachko, N. F., McMillan, P. J., Strovas, T. J., Loomis, E., Greenup, L., Murrell, J. R., ... 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

The Tau Tubulin Kinases TTBK1/2 Promote Accumulation of Pathological TDP-43. / Liachko, Nicole F.; McMillan, Pamela J.; Strovas, Timothy J.; Loomis, Elaine; Greenup, Lynne; Murrell, Jill R.; Ghetti, Bernardino; Raskind, Murray A.; Montine, Thomas J.; Bird, Thomas D.; Leverenz, James B.; Kraemer, Brian C.

In: PLoS Genetics, Vol. 10, No. 12, 01.12.2014.

Research output: Contribution to journalArticle

Liachko, NF, McMillan, PJ, Strovas, TJ, Loomis, E, Greenup, L, Murrell, JR, Ghetti, B, Raskind, MA, Montine, TJ, Bird, TD, Leverenz, JB & Kraemer, BC 2014, 'The Tau Tubulin Kinases TTBK1/2 Promote Accumulation of Pathological TDP-43', PLoS Genetics, vol. 10, no. 12. https://doi.org/10.1371/journal.pgen.1004803
Liachko NF, McMillan PJ, Strovas TJ, Loomis E, Greenup L, Murrell JR et al. The Tau Tubulin Kinases TTBK1/2 Promote Accumulation of Pathological TDP-43. PLoS Genetics. 2014 Dec 1;10(12). https://doi.org/10.1371/journal.pgen.1004803
Liachko, Nicole F. ; McMillan, Pamela J. ; Strovas, Timothy J. ; Loomis, Elaine ; Greenup, Lynne ; Murrell, Jill R. ; Ghetti, Bernardino ; Raskind, Murray A. ; Montine, Thomas J. ; Bird, Thomas D. ; Leverenz, James B. ; Kraemer, Brian C. / The Tau Tubulin Kinases TTBK1/2 Promote Accumulation of Pathological TDP-43. In: PLoS Genetics. 2014 ; Vol. 10, No. 12.
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