The DOI matches its Crossref record; 8 of the 8 references it cites were found in a registry or an index.
Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity
Open accessAbstract
Inclusions of TAR DNA-binding protein-43 (TDP-43), a nuclear protein that regulates transcription and RNA splicing, are the defining histopathological feature of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-Us) and sporadic and familial forms of amyotrophic lateral sclerosis (ALS). In ALS and FTLD-U, aggregated, ubiquitinated, and N-terminally truncated TDP-43 can be isolated from brain tissue rich in neuronal and glial cytoplasmic inclusions. The loss of TDP-43 function resulting from inappropriate cleavage, translocation from the nucleus, or its sequestration into inclusions could play important roles in neurodegeneration. However, it is not known whether TDP-43 fragments directly mediate toxicity and, more specifically, whether their abnormal aggregation is a cause or consequence of pathogenesis. We report that the ectopic expression of a ≈25-kDa TDP-43 fragment corresponding to the C-terminal truncation product of caspase-cleaved TDP-43 leads to the formation of toxic, insoluble, and ubiquitin- and phospho-positive cytoplasmic inclusions within cells. The 25-kDa C-terminal fragment is more prone to phosphorylation at S409/S410 than full-length TDP-43, but phosphorylation at these sites is not required for inclusion formation or toxicity. Although this fragment shows no biological activity, its exogenous expression neither inhibits the function nor causes the sequestration of full-length nuclear TDP-43, suggesting that the 25-kDa fragment can induce cell death through a toxic gain-of-function. Finally, by generating a conformation-dependent antibody that detects C-terminal fragments, we show that this toxic cleavage product is specific for pathologic inclusions in human TDP-43 proteinopathies.
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Cites
Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis
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Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17
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Self-citationArai, T., Hasegawa, M., Akiyama, H., Ikeda, K., Nonaka, T., Mori, H., Mann, D., Tsuchiya, K., Yoshida, M., Hashizume, Y., et al. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.10.093 · Cited by 2,732
TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis
Sreedharan, J., Blair, I. P., Tripathi, V. B., Hu, X., Vance, C., Rogelj, B., Ackerley, S., Durnall, J. C., Williams, K. L., Buratti, E., et al. (2008) · Science · doi:10.1126/science.1154584 · Cited by 2,630
Self-citationTARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis
Kabashi, E., Valdmanis, P. N., Dion, P., Spiegelman, D., McConkey, B. J., Velde, C. V., Bouchard, J.-P., Lacomblez, L., Pochigaeva, K., Salachas, F., et al. (2008) · Nature Genetics · doi:10.1038/ng.132 · Cited by 1,544
Phosphorylated TDP‐43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis
Hasegawa, M., Arai, T., Nonaka, T., Kametani, F., Yoshida, M., Hashizume, Y., Beach, T. G., Buratti, E., Baralle, F., Morita, M., et al. (2008) · Annals of Neurology · doi:10.1002/ana.21425 · Cited by 777
Self-citationTDP ‐ 43 mutation in familial amyotrophic lateral sclerosis
Yokoseki, A., Shiga, A., Tan, C., Tagawa, A., Kaneko, H., Koyama, A., Eguchi, H., Tsujino, A., Ikeuchi, T., Kakita, A., et al. (2008) · Annals of Neurology · doi:10.1002/ana.21392 · Cited by 373
Cited by
TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration
Lagier-Tourenne, C., Polymenidou, M., & Cleveland, D. W. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq137 · Cited by 1,021
Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis
Prasad, A., Bharathi, V., Sivalingam, V., Girdhar, A., & Patel, B. K. (2019) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2019.00025 · Cited by 774
TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration
Wegorzewska, I., Bell, S., Cairns, N. J., Miller, T. M., & Baloh, R. H. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0908767106 · Cited by 706
Gains or losses: molecular mechanisms of TDP43-mediated neurodegeneration
Lee, E. B., Lee, V. M.-Y., & Trojanowski, J. Q. (2012) · Nature Reviews Neuroscience · doi:10.1038/nrn3121 · Cited by 659
Liu-Yesucevitz, L., Bilgutay, A., Zhang, Y.-J., Vanderwyde, T., Citro, A., Mehta, T., Zaarur, N., McKee, A., Bowser, R., Sherman, M., et al. (2010) · PLoS ONE · doi:10.1371/journal.pone.0013250 · Cited by 620
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Metadata
- Authors
- Zhang, Y.-J., Xu, Y.-F., Cook, C., Gendron, T. F., Roettges, P., Link, C. D., Lin, W.-L., Tong, J., Castanedes-Casey, M., Ash, P., Gass, J., Rangachari, V., Buratti, E., Baralle, F., Golde, T. E., Dickson, D. W., & Petrucelli, L.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2009-05-05
- Volume
- 106
- Issue
- 18
- Pages
- 7607-7612
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2131725903
- Cited by
- 604
- References
- 8
- FWCI
- 27.19
- Type
- journal article
- Language
- en
- Open access
- green
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- Zhang, Y.-J., Xu, Y.-F., Cook, C., Gendron, T. F., Roettges, P., Link, C. D., Lin, W.-L., Tong, J., Castanedes-Casey, M., Ash, P., Gass, J., Rangachari, V., Buratti, E., Baralle, F., Golde, T. E., Dickson, D. W., & Petrucelli, L. (2009). Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.0900688106
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