| RRC ID |
45790
|
| Author |
Liachko NF, McMillan PJ, Strovas TJ, Loomis E, Greenup L, Murrell JR, Ghetti B, Raskind MA, Montine TJ, Bird TD, Leverenz JB, Kraemer BC.
|
| Title |
The tau tubulin kinases TTBK1/2 promote accumulation of pathological TDP-43.
|
| Journal |
PLoS Genet
|
| 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.
|
| Volume |
10(12)
|
| Pages |
e1004803
|
| Published |
2014-12-1
|
| DOI |
10.1371/journal.pgen.1004803
|
| PII |
PGENETICS-D-14-01060
|
| PMID |
25473830
|
| PMC |
PMC4256087
|
| MeSH |
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
|
| IF |
5.175
|
| Times Cited |
43
|
|
WOS Category
|
GENETICS & HEREDITY
|
| Resource |
| C.elegans |
tm4391
tm4720
tm4076
tm4396 |
