論文 - 詳細
| RRC ID | 53843 |
|---|---|
| 著者 | McGurk L, Gomes E, Guo L, Mojsilovic-Petrovic J, Tran V, Kalb RG, Shorter J, Bonini NM. |
| タイトル | Poly(ADP-Ribose) Prevents Pathological Phase Separation of TDP-43 by Promoting Liquid Demixing and Stress Granule Localization. |
| ジャーナル | Mol Cell |
| Abstract |
In amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD), cytoplasmic aggregates of hyperphosphorylated TDP-43 accumulate and colocalize with some stress granule components, but how pathological TDP-43 aggregation is nucleated remains unknown. In Drosophila, we establish that downregulation of tankyrase, a poly(ADP-ribose) (PAR) polymerase, reduces TDP-43 accumulation in the cytoplasm and potently mitigates neurodegeneration. We establish that TDP-43 non-covalently binds to PAR via PAR-binding motifs embedded within its nuclear localization sequence. PAR binding promotes liquid-liquid phase separation of TDP-43 in vitro and is required for TDP-43 accumulation in stress granules in mammalian cells and neurons. Stress granule localization initially protects TDP-43 from disease-associated phosphorylation, but upon long-term stress, stress granules resolve, leaving behind aggregates of phosphorylated TDP-43. Finally, small-molecule inhibition of Tankyrase-1/2 in mammalian cells inhibits formation of cytoplasmic TDP-43 foci without affecting stress granule assembly. Thus, Tankyrase inhibition antagonizes TDP-43-associated pathology and neurodegeneration and could have therapeutic utility for ALS and FTD. |
| 巻・号 | 71(5) |
| ページ | 703-717.e9 |
| 公開日 | 2018-9-6 |
| DOI | 10.1016/j.molcel.2018.07.002 |
| PII | S1097-2765(18)30549-5 |
| PMID | 30100264 |
| PMC | PMC6128762 |
| MeSH | Amyotrophic Lateral Sclerosis / metabolism Animals COS Cells Cell Line Cell Nucleus / metabolism Chlorocebus aethiops Cytoplasm / metabolism DNA-Binding Proteins / metabolism* Drosophila Female Frontotemporal Lobar Degeneration / metabolism Male Mammals / metabolism Neurodegenerative Diseases / metabolism Neurons / metabolism Phosphorylation / physiology Poly Adenosine Diphosphate Ribose / metabolism* Rats Rats, Sprague-Dawley |
| IF | 15.584 |
| 引用数 | 69 |
| 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 | 113 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 7.0 |
| リソース情報 | |
| ショウジョウバエ | 4179R-4 |