Hetero-oligomerization of TDP-43 carboxy-terminal fragments with cellular proteins contributes to proteotoxicity

Akira Kitamura; Ai Fujimoto; Rei Kawashima; Yidan Lyu; Kotetsu Sasaki; Yuta Hamada; Kanami Moriya; Ayumi Kurata; Kazuho Takahashi; Reneé Brielmann; Laura C. Bott; Richard I. Morimoto; Masataka Kinjo

doi:10.1038/s42003-024-06410-3

Hetero-oligomerization of TDP-43 carboxy-terminal fragments with cellular proteins contributes to proteotoxicity

Akira Kitamura^*, Ai Fujimoto, Rei Kawashima, Yidan Lyu, Kotetsu Sasaki, Yuta Hamada, Kanami Moriya, Ayumi Kurata, Kazuho Takahashi, Reneé Brielmann, Laura C. Bott, Richard I. Morimoto, Masataka Kinjo

^*Corresponding author for this work

Molecular Biosciences

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

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.

Original language	English (US)
Article number	743
Journal	Communications Biology
Volume	7
Issue number	1
DOIs	https://doi.org/10.1038/s42003-024-06410-3
State	Published - Dec 2024

Funding

We thank Rintaro Kawamura for insightful discussions and Sue Fox for technical support. The authors acknowledge Open Facility Division, Global Facility Center, Creative Research Institution, and Hokkaido University for the use of a chemiluminescence imager. A.K. was supported by grants from the Japan Agency for Medical Research and Development (JP22gm6410028 and JP22ym0126814); a Japan Society for Promotion of Science (JSPS) Grant-in-Aid for Transformative Research Areas (A) (24H02286); Grant-in-Aid for Scientific Research on Innovative Areas (22H04826); a JSPS Grant-in-Aid for the Promotion of Joint International Research (Fostering Joint International Research) (16KK0156); a JSPS Grant-in-Aid for Scientific Research (C) (18K06201); a grant from Hokkaido University Office for Developing Future Research Leaders (L-Station); a grant from Canon Foundation; a grant from Hoansha Foundation; a grant from Hagiwara Foundation of Japan; a grant from Nakatani Foundation. M.K. was partially supported by a JSPS Grant-in-Aid for Scientific Research (B) (22H02578) and a JSPS Grant-in-Aid for Challenging Research (Exploratory) (22K19886); A.F. was supported by the Support for Pioneering Research Initiated by the Next Generation (SPRING) program by the Japan Science and Technology Agency (JST) in Hokkaido University (JPMJSP2119); and Y.H. was supported by the establishment of universities fellowship toward the creation of science technology innovation (the Hokkaido University Ambitious Doctoral Fellowship) supported by the Japan Science and Technology Agency (JST) (JPMJFS2101).

ASJC Scopus subject areas

Medicine (miscellaneous)
General Biochemistry, Genetics and Molecular Biology
General Agricultural and Biological Sciences

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Kitamura, A., Fujimoto, A., Kawashima, R., Lyu, Y., Sasaki, K., Hamada, Y., Moriya, K., Kurata, A., Takahashi, K., Brielmann, R., Bott, L. C., Morimoto, R. I., & Kinjo, M. (2024). Hetero-oligomerization of TDP-43 carboxy-terminal fragments with cellular proteins contributes to proteotoxicity. Communications Biology, 7(1), Article 743. https://doi.org/10.1038/s42003-024-06410-3

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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.",

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AU - Kitamura, Akira

AU - Fujimoto, Ai

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AU - Sasaki, Kotetsu

AU - Hamada, Yuta

AU - Moriya, Kanami

AU - Kurata, Ayumi

AU - Takahashi, Kazuho

AU - Brielmann, Reneé

AU - Bott, Laura C.

AU - Morimoto, Richard I.

AU - Kinjo, Masataka

PY - 2024/12

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N2 - 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.

AB - 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.

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Hetero-oligomerization of TDP-43 carboxy-terminal fragments with cellular proteins contributes to proteotoxicity

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