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

• Published in: Acta neuropathologica communications 2019-07, Vol.7 (1), p.118-118, Article 118
• Main Authors: Nishino, Kohei, Watanabe, Seiji, Shijie, Jin, Murata, Yuri, Oiwa, Kotaro, Komine, Okiru, Endo, Fumito, Tsuiji, Hitomi, Abe, Manabu, Sakimura, Kenji, Mishra, Amit, Yamanaka, Koji
• Format: Article
• Language: English
• Subjects: Age Factors; Akt; Amyotrophic lateral sclerosis; Amyotrophic lateral sclerosis (ALS); Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Animals; Binding proteins; Cell Line, Tumor; Cells, Cultured; Disease Models, Animal; DNA; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - genetics; EDTA; Gene expression; Gene Knock-In Techniques; Medical research; Messenger RNA; Mice; Mice, Inbred C57BL; Motor dysfunction; Neomycin; Neurons; Notch1; Protein binding; Proto-Oncogene Proteins c-akt - biosynthesis; Proto-Oncogene Proteins c-akt - genetics; Receptor, Notch1 - biosynthesis; Receptor, Notch1 - genetics; RNA; Signal Transduction - physiology; TAR DNA-binding protein 43 (TDP-43); TDP-43 knock-in mice
• ISSN: 2051-5960; 2051-5960
• DOI: 10.1186/s40478-019-0776-5

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 α-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.