| 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
|
| Resource |
| Human and Animal Cells |
201B7(HPS0063) |
| DNA material |
CSII-EF-MCS-IRES2-Venus (RDB04384)
pCMV-VSV-G-RSV-Rev (RDB04393)
pCAG-HIVgp (RDB04394) |
