The tau tubulin kinases TTBK1/2 promote accumulation of pathological TDP-43

PLoS Genet. 2014 Dec 4;10(12):e1004803. doi: 10.1371/journal.pgen.1004803. eCollection 2014 Dec.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism
  • Animals
  • Animals, Genetically Modified
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism
  • Cells, Cultured
  • DNA-Binding Proteins / metabolism*
  • Frontotemporal Dementia / genetics
  • Frontotemporal Dementia / metabolism
  • Frontotemporal Lobar Degeneration / genetics
  • Frontotemporal Lobar Degeneration / metabolism
  • Gene Expression Profiling
  • HEK293 Cells
  • Humans
  • Mice
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Serine-Threonine Kinases / physiology*
  • Proteolysis
  • RNA Interference

Substances

  • DNA-Binding Proteins
  • tau-tubulin kinase
  • Protein-Serine-Threonine Kinases