The DOI matches its Crossref record; 7 of the 7 references it cites were found in a registry or an index.
Phase separation-deficient TDP43 remains functional in splicing
Open accessAbstract
Intrinsically disordered regions (IDRs) are often fast-evolving protein domains of low sequence complexity that can drive phase transitions and are commonly found in many proteins associated with neurodegenerative diseases, including the RNA processing factor TDP43. Yet, how phase separation contributes to the physiological functions of TDP43 in cells remains enigmatic. Here, we combine systematic mutagenesis guided by evolutionary sequence analysis with a live-cell reporter assay of TDP43 phase dynamics to identify regularly-spaced hydrophobic motifs separated by flexible, hydrophilic segments in the IDR as a key determinant of TDP43 phase properties. This heuristic framework allows customization of the material properties of TDP43 condensates to determine effects on splicing function. Remarkably, even a mutant that fails to phase-separate at physiological concentrations can still efficiently mediate the splicing of a quantitative, single-cell splicing reporter and endogenous targets. This suggests that the ability of TDP43 to phase-separate is not essential for its splicing function.
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Cites
Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis
Neumann, M., Sampathu, D. M., Kwong, L. K., Truax, A. C., Micsenyi, M. C., Chou, T. T., Bruce, J., Schuck, T., Grossman, M., Clark, C. M., et al. (2006) · Science · doi:10.1126/science.1134108 · Cited by 6,576
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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
TARDBP 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
Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43
Polymenidou, M., Lagier-Tourenne, C., Hutt, K. R., Huelga, S. C., Moran, J., Liang, T. Y., Ling, S.-C., Sun, E., Wancewicz, E., Mazur, C., et al. (2011) · Nature Neuroscience · doi:10.1038/nn.2779 · Cited by 1,335
Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice
Becker, L. A., Huang, B., Bieri, G., Ma, R., Knowles, D. A., Jafar-Nejad, P., Messing, J., Kim, H. J., Soriano, A., Auburger, G., et al. (2017) · Nature · doi:10.1038/nature22038 · Cited by 571
Relationship of sequence and phase separation in protein low-complexity regions
Martin, E. W., & Mittag, T. (2018) · Biochemistry · doi:10.1021/acs.biochem.8b00008 · Cited by 389
Cited by
TDP-43 represses cryptic exon inclusion in the FTD-ALS gene UNC13A
Ma, X. R., Prudencio, M., Koike, Y., Vatsavayai, S. C., Kim, G., Harbinski, F., Briner, A., Rodriguez, C. M., Guo, C., Akiyama, T., et al. (2022) · Nature · doi:10.1038/s41586-022-04424-7 · Cited by 574
Self-citationPhase separation and neurodegenerative diseases: a disturbance in the force
Zbinden, A., Pérez-Berlanga, M., De Rossi, P., & Polymenidou, M. (2020) · Developmental Cell · doi:10.1016/j.devcel.2020.09.014 · Cited by 500
HSP70 chaperones RNA-free TDP-43 into anisotropic intranuclear liquid spherical shells
Yu, H., Lu, S., Gasior, K., Singh, D., Vazquez-Sanchez, S., Tapia, O., Toprani, D., Beccari, M. S., Yates, J. R., Da Cruz, S., et al. (2021) · Science · doi:10.1126/science.abb4309 · Cited by 353
Conformational ensembles of the human intrinsically disordered proteome
Tesei, G., Trolle, A. I., Jonsson, N., Betz, J., Knudsen, F. E., Pesce, F., Johansson, K. E., & Lindorff-Larsen, K. (2024) · Nature · doi:10.1038/s41586-023-07004-5 · Cited by 308
Martin, E. W., & Holehouse, A. S. (2020) · Emerging Topics in Life Sciences · doi:10.1042/etls20190164 · Cited by 281
Metadata
- Authors
- Schmidt, H. B., Barreau, A., & Rohatgi, R.
- Venue
- Nature Communications
- Published
- 2019-10-25
- Volume
- 10
- Issue
- 1
- Pages
- 4890-4890
- ISSN
- 2041-1723 (ISSN-L)
- OpenAlex
- W2981963645
- Cited by
- 178
- References
- 7
- FWCI
- 5.59
- Type
- journal article
- Language
- en
- Open access
- gold
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