| First Author | Nishino K | Year | 2019 |
| Journal | Acta Neuropathol Commun | Volume | 7 |
| Issue | 1 | Pages | 118 |
| PubMed ID | 31345270 | Mgi Jnum | J:283597 |
| Mgi Id | MGI:6355717 | Doi | 10.1186/s40478-019-0776-5 |
| Citation | Nishino K, et al. (2019) Mice deficient in the C-terminal domain of TAR DNA-binding protein 43 develop age-dependent motor dysfunction associated with impaired Notch1-Akt signaling pathway. Acta Neuropathol Commun 7(1):118 |
| abstractText | Intracellular mislocalization of TAR DNA-binding protein 43 (TDP-43), a nuclear DNA/RNA-binding protein involved in RNA metabolism, is a pathological hallmark of amyotrophic lateral sclerosis (ALS). Although the aggregation-prone, TDP-43 C-terminal domain is widely considered as a key component of TDP-43 pathology in ALS, recent studies including ours suggest that TDP-43 N-terminal fragments (TDP-C) may also contribute to the motor dysfunction in ALS. However, the specific pathological functions of TDP-43 N-terminal fragments in mice have not been elucidated. Here, we established TDP-C knock-in mice missing a part of exon 6 of murine Tardbp gene, which encodes the C-terminal region of TDP-43. Homozygous TDP-C mice showed embryonic lethality, indicating that the N-terminal domain of TDP-43 alone is not sufficient for normal development. In contrast, heterozygous TDP-C mice developed normally but exhibited age-dependent mild motor dysfunction with a loss of C-boutons, large cholinergic synaptic terminals on spinal alpha-motor neurons. TDP-C protein broadly perturbed gene expression in the spinal cords of aged heterozygous TDP-C mice, including downregulation of Notch1 mRNA. Moreover, the level of Notch1 mRNA was suppressed both by TDP-43 depletion and TDP-C expression in Neuro2a cells. Decreased Notch1 mRNA expression in aged TDP-C mice was associated with the age-dependent motor dysfunction and loss of Akt surviving signal. Our findings indicate that the N-terminal region of TDP-43 derived from TDP-C induces the age-dependent motor dysfunction associated with impaired Notch1-Akt axis in mice. |
