論文 - 詳細
| RRC ID | 76692 |
|---|---|
| 著者 | Oiwa K, Watanabe S, Onodera K, Iguchi Y, Kinoshita Y, Komine O, Sobue A, Okada Y, Katsuno M, Yamanaka K. |
| タイトル | Monomerization of TDP-43 is a key determinant for inducing TDP-43 pathology in amyotrophic lateral sclerosis. |
| ジャーナル | Sci Adv |
| Abstract |
The cytoplasmic aggregation of TAR DNA binding protein-43 (TDP-43), also known as TDP-43 pathology, is the pathological hallmark of amyotrophic lateral sclerosis (ALS). However, the mechanism underlying TDP-43 cytoplasmic mislocalization and subsequent aggregation remains unclear. Here, we show that TDP-43 dimerization/multimerization is impaired in the postmortem brains and spinal cords of patients with sporadic ALS and that N-terminal dimerization-deficient TDP-43 consists of pathological inclusion bodies in ALS motor neurons. Expression of N-terminal dimerization-deficient mutant TDP-43 in Neuro2a cells and induced pluripotent stem cell-derived motor neurons recapitulates TDP-43 pathology, such as Nxf1-dependent cytoplasmic mislocalization and aggregate formation, which induces seeding effects. Furthermore, TDP-DiLuc, a bimolecular luminescence complementation reporter assay, could detect decreased N-terminal dimerization of TDP-43 before TDP-43 pathological changes caused by the transcription inhibition linked to aberrant RNA metabolism in ALS. These findings identified TDP-43 monomerization as a critical determinant inducing TDP-43 pathology in ALS. |
| 巻・号 | 9(31) |
| ページ | eadf6895 |
| 公開日 | 2023-8-4 |
| DOI | 10.1126/sciadv.adf6895 |
| PMID | 37540751 |
| PMC | PMC10403219 |
| MeSH | Amyotrophic Lateral Sclerosis* / genetics Amyotrophic Lateral Sclerosis* / pathology DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism Humans Inclusion Bodies / metabolism Motor Neurons / metabolism |
| IF | 13.117 |
| 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 | 72 |
| 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 | |
| ヒト・動物細胞 | 201B7(HPS0063) |
| 遺伝子材料 | CSII-EF-MCS-IRES2-Venus (RDB04384) pCMV-VSV-G-RSV-Rev (RDB04393) pCAG-HIVgp (RDB04394) |