Importance of the Q/N-rich segment for protein stability of endogenous mouse TDP-43.
Sci Rep
; 12(1): 14923, 2022 Sep 02.
Article
em En
| MEDLINE
| ID: mdl-36056157
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas de Ligação a DNA
/
Estabilidade Proteica
Limite:
Animals
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article