Importance of the Q/N-rich segment for protein stability of endogenous mouse TDP-43

• Published in: Scientific reports 2022-09, Vol.12 (1), p.14923-14923, Article 14923
• Main Authors: Sato, Toshiya, Oda, Kanako, Sakai, Seiko, Kato, Rika, Yamamori, Saori, Itakura, Makoto, Kodera, Yoshio, Nishizawa, Masatoyo, Sasaoka, Toshikuni, Onodera, Osamu, Yokoyama, Minesuke
• Format: Article
• Language: English
• Subjects: 631/1647/767/1424; 631/1647/767/1658; 631/378/1689/1285; Humanities and Social Sciences; multidisciplinary; Science; Science (multidisciplinary)
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-19153-0

TAR DNA-binding protein 43 kDa (TDP-43), a nuclear protein, plays an important role in the molecular pathogenesis of amyotrophic lateral sclerosis (ALS). The long-disordered C-terminal region (CTR) of TDP-43 is known to be aggregation-prone and a hotspot for ALS mutations, so elucidation of the physiological function of CTR will provide insights into the pathogenesis of ALS. The CTR has two Gly, aromatic, and Ser-rich (GaroS) segments and an amyloidogenic core divided into a hydrophobic patch (HP) and a Gln/Asn (Q/N)-rich segment. Although TDP-43 lacking the CTR is known to be unstable, as observed in knock-in mice, it is unclear which of these segments contributes to the stability of TDP-43. Here, we generated 12 mouse lines lacking the various sub-regions of CTR by genome editing and compared the embryonic lethality of homozygotes, and protein and mRNA expression levels of TDP-43. We demonstrated the functional diversity of the four segments of CTR, finding that the presence of the Q/N-rich segment greatly restored the protein stability of TDP-43. In addition, we found that the second GaroS deletion did not affect protein stability and mouse development.