2022.09.20

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

Sci Rep. 2022 Sep 2;12(1):14923. doi: 10.1038/s41598-022-19153-0.

Sato T1,2,3, Oda K3, Sakai S3, Kato R2, Yamamori S4, Itakura M4, Kodera Y5, Nishizawa M6,7, Sasaoka T3, Onodera O6, Yokoyama M3,8.

1Department of Laboratory Animal Science, Kitasato University School of Medicine
2Center for Genetic Studies of Integrated Biological Functions, Kitasato University School of Medicine
3Department of Comparative and Experimental Medicine, Brain Research Institute, Niigata University
4Department of Biochemistry, Kitasato University School of Medicine
5Department of Physics, Kitasato University School of Science
6Department of Neurology, Brain Research Institute, Niigata University
7Department of Nursing, Niigata University of Health and Welfare
8Central Institute for Experimental Animals

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.

*Reprinted under the terms of the Creative Commons Attribution License (CC BY).

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