The DOI matches its Crossref record; 11 of the 11 references it cites were found in a registry or an index.
Interaction with Polyglutamine Aggregates Reveals a Q/N-rich Domain in TDP-43
Open accessAbstract
The identification of pathologic TDP-43 aggregates in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration, followed by the discovery of dominantly inherited point mutations in TDP-43 in familial ALS, have been critical insights into the mechanism of these untreatable neurodegenerative diseases. However, the biochemical basis of TDP-43 aggregation and the mechanism of how mutations in TDP-43 lead to disease remain enigmatic. In efforts to understand how TDP-43 alters its cellular localization in response to proteotoxic stress, we found that TDP-43 is sequestered into polyglutamine aggregates. Furthermore, we found that binding to polyglutamine aggregates requires a previously uncharacterized glutamine/asparagine (Q/N)-rich region in the C-terminal domain of TDP-43. Sequestration into polyglutamine aggregates causes TDP-43 to be cleared from the nucleus and become detergent-insoluble. Finally, we observed that sequestration into polyglutamine aggregates led to loss of TDP-43-mediated splicing in the nucleus and that polyglutamine toxicity could be partially rescued by increasing expression of TDP-43. These data indicate pathologic sequestration into polyglutamine aggregates, and loss of nuclear TDP-43 function may play an unexpected role in polyglutamine disease pathogenesis. Furthermore, as Q/N domains have a strong tendency to self-aggregate and in some cases can function as prions, the identification of a Q/N domain in TDP-43 has important implications for the mechanism of pathologic aggregation of TDP-43 in ALS and other neurodegenerative diseases.
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Cites
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TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis
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Self-citationCo-morbidity of TDP-43 proteinopathy in Lewy body related diseases
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Cited by
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
Protein aggregation in amyotrophic lateral sclerosis
Blokhuis, A. M., Groen, E. J. N., Koppers, M., van den Berg, L. H., & Pasterkamp, R. J. (2013) · Acta Neuropathologica · doi:10.1007/s00401-013-1125-6 · Cited by 579
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TDP-43 Proteinopathy and ALS: Insights into Disease Mechanisms and Therapeutic Targets
Scotter, E. L., Chen, H.-J., & Shaw, C. E. (2015) · Neurotherapeutics · doi:10.1007/s13311-015-0338-x · Cited by 382
Metadata
- Authors
- Fuentealba, R. A., Udan, M., Bell, S., Wegorzewska, I., Shao, J., Diamond, M. I., Weihl, C. C., & Baloh, R. H.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2010-08
- Volume
- 285
- Issue
- 34
- Pages
- 26304-26314
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2157450464
- Cited by
- 158
- References
- 11
- FWCI
- 8.86
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Fuentealba, R. A., Udan, M., Bell, S., Wegorzewska, I., Shao, J., Diamond, M. I., Weihl, C. C., & Baloh, R. H. (2010). Interaction with Polyglutamine Aggregates Reveals a Q/N-rich Domain in TDP-43. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.m110.125039
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
