Reference - Detail
| RRC ID | 76692 |
|---|---|
| Author | Oiwa K, Watanabe S, Onodera K, Iguchi Y, Kinoshita Y, Komine O, Sobue A, Okada Y, Katsuno M, Yamanaka K. |
| Title | Monomerization of TDP-43 is a key determinant for inducing TDP-43 pathology in amyotrophic lateral sclerosis. |
| Journal | 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. |
| Volume | 9(31) |
| Pages | eadf6895 |
| Published | 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 |
| Altmetric score |
オルトメトリクス指標項目
|
| The most frequently cited source | X(Twitter) |
| Total number of mentions | 72 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | 201B7(HPS0063) |
| DNA material | CSII-EF-MCS-IRES2-Venus (RDB04384) pCMV-VSV-G-RSV-Rev (RDB04393) pCAG-HIVgp (RDB04394) |