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

AI Article Synopsis

  • TDP-43 is a nuclear protein linked to the molecular development of amyotrophic lateral sclerosis (ALS), with its long C-terminal region (CTR) being critical for its stability and associated with ALS mutations.
  • Researchers created 12 mouse models lacking different sub-regions of the CTR to study their effects on TDP-43's protein stability and embryonic lethality.
  • They discovered that the Q/N-rich segment of the CTR significantly enhances TDP-43 stability, while the absence of the second GaroS segment does not impact protein stability or mouse development.

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9440050PMC
http://dx.doi.org/10.1038/s41598-022-19153-0DOI Listing

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