1. Importance of the Q/N-rich segment for protein stability of endogenous mouse TDP-43.
- Author
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Sato, Toshiya, Oda, Kanako, Sakai, Seiko, Kato, Rika, Yamamori, Saori, Itakura, Makoto, Kodera, Yoshio, Nishizawa, Masatoyo, Sasaoka, Toshikuni, Onodera, Osamu, and Yokoyama, Minesuke
- Subjects
DNA-binding proteins ,MICE ,GENE expression ,PROTEIN expression ,NUCLEAR proteins ,AMYOTROPHIC lateral sclerosis ,PROTEIN stability - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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