論文 - 詳細
| RRC ID | 45790 |
|---|---|
| 著者 | Liachko NF, McMillan PJ, Strovas TJ, Loomis E, Greenup L, Murrell JR, Ghetti B, Raskind MA, Montine TJ, Bird TD, Leverenz JB, Kraemer BC. |
| タイトル | The tau tubulin kinases TTBK1/2 promote accumulation of pathological TDP-43. |
| ジャーナル | 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. |
| 巻・号 | 10(12) |
| ページ | e1004803 |
| 公開日 | 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 |
| 引用数 | 43 |
| WOS 分野 | GENETICS & HEREDITY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 6 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 線虫 | tm4391 tm4720 tm4076 tm4396 |