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- Title
Hetero-oligomerization of TDP-43 carboxy-terminal fragments with cellular proteins contributes to proteotoxicity.
- Authors
Kitamura, Akira; Fujimoto, Ai; Kawashima, Rei; Lyu, Yidan; Sasaki, Kotetsu; Hamada, Yuta; Moriya, Kanami; Kurata, Ayumi; Takahashi, Kazuho; Brielmann, Reneé; Bott, Laura C.; Morimoto, Richard I.; Kinjo, Masataka
- Abstract
Carboxy terminal fragments (CTFs) of TDP-43 contain an intrinsically disordered region (IDR) and form cytoplasmic condensates containing amyloid fibrils. Such condensates are toxic and associated with pathogenicity in amyotrophic lateral sclerosis. However, the molecular details of how the domain of TDP-43 CTFs leads to condensation and cytotoxicity remain elusive. Here, we show that truncated RNA/DNA-recognition motif (RRM) at the N-terminus of TDP-43 CTFs leads to the structural transition of the IDR, whereas the IDR itself of TDP-43 CTFs is difficult to assemble even if they are proximate intermolecularly. Hetero-oligomers of TDP-43 CTFs that have recruited other proteins are more toxic than homo-oligomers, implicating loss-of-function of the endogenous proteins by such oligomers is associated with cytotoxicity. Furthermore, such toxicity of TDP-43 CTFs was cell-nonautonomously affected in the nematodes. Therefore, misfolding and oligomeric characteristics of the truncated RRM at the N-terminus of TDP-43 CTFs define their condensation properties and toxicity. Immortalized cell lines and Caenorhabditis elegans are employed to characterize the aggregation properties and toxicity associated with the C-terminal fragment of TDP-43, a gene product implicated in ALS.
- Subjects
AMYOTROPHIC lateral sclerosis; CYTOTOXINS; CAENORHABDITIS elegans; PROTEINS; CELL lines; AMYLOID beta-protein
- Publication
Communications Biology, 2024, Vol 7, Issue 1, p1
- ISSN
2399-3642
- Publication type
Article
- DOI
10.1038/s42003-024-06410-3