The DOI matches its Crossref record; 31 of the 31 references it cites were found in a registry or an index.
Structural determinants of the cellular localization and shuttling of TDP-43
Abstract
TDP-43 (also known as TARDBP) regulates different processes of gene expression, including transcription and splicing, through RNA and DNA binding. Moreover, recent reports have shown that the protein interacts with the 3′UTRs of specific mRNAs. The aberrant cellular distribution and aggregation of TDP-43 were recently reported in neurodegenerative diseases, namely frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). A detailed description of the determinants for cellular localization has yet to emerge, including information on how the known functions of TDP-43 and cellular targeting affect each other. We provide the first experimental evidence that TDP-43 continuously shuttles between nucleus and cytoplasm in a transcription-dependent manner. Furthermore, we investigate the role of the functional TDP-43 domains in determining cellular targeting through a combination of immunofluorescence and biochemical fractionation methods. Our analyses indicate that the C-terminus is essential for solubility and cellular localization, because its deletion results in the formation of large nuclear and cytoplasmic aggregates. Disruption of the RNA-recognition domain required for RNA and DNA binding, however, alters nuclear distribution by decreasing TDP-43 presence in the nucleoplasm. Our findings suggest that TDP-43 solubility and localization are particularly sensitive to disruptions that extend beyond the newly found nuclear localization signal and depend on a combination of factors that are closely connected to the functional properties of this protein.
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Cites
Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis
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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
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
Shuttling of pre-mRNA binding proteins between nucleus and cytoplasm
Piñol-Roma, S., & Dreyfuss, G. (1992) · Nature · doi:10.1038/355730a0 · Cited by 834
hnRNP complexes: composition, structure, and function
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Self-citationWinton, M. J., Igaz, L. M., Wong, M. M., Kwong, L. K., Trojanowski, J. Q., & Lee, V. M.-Y. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m800342200 · Cited by 659
Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping
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Cited by
Converging Mechanisms in ALS and FTD: Disrupted RNA and Protein Homeostasis
Ling, S.-C., Polymenidou, M., & Cleveland, D. W. (2013) · Neuron · doi:10.1016/j.neuron.2013.07.033 · Cited by 1,811
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
ALS‐associated fused in sarcoma (FUS) mutations disrupt Transportin‐mediated nuclear import
Dormann, D., Rodde, R., Edbauer, D., Bentmann, E., Fischer, I., Hruscha, A., Than, M. E., Mackenzie, I. R. A., Capell, A., Schmid, B., et al. (2010) · The EMBO Journal · doi:10.1038/emboj.2010.143 · Cited by 836
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
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
Metadata
- Authors
- Ayala, Y. M., Zago, P., D'Ambrogio, A., Xu, Y.-F., Petrucelli, L., Buratti, E., & Baralle, F. E.
- Venue
- Journal of Cell Science
- Publisher
- The Company of Biologists
- Published
- 2008-11-15
- Volume
- 121
- Issue
- 22
- Pages
- 3778-3785
- ISSN
- 0021-9533 (ISSN-L)
- 1477-9137
- OpenAlex
- W2154417593
- Cited by
- 630
- References
- 31
- FWCI
- 15.13
- Type
- journal article
- Language
- en
- Open access
- closed
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