The DOI matches its Crossref record; 64 of the 64 references it cites were found in a registry or an index.
RNA Binding Antagonizes Neurotoxic Phase Transitions of TDP-43
Open accessAbstract
Summary TDP-43 proteinopathy is a pathological hallmark of ALS/FTD where cytoplasmic TDP-43 inclusions are observed within degenerating regions of patient postmortem tissue. The mechanism by which TDP-43 aggregates has remained elusive due to technological limitations which prevent the analysis of specific TDP-43 interactions in live cells. We present an optogenetic approach to reliably induce TDP-43 proteinopathy under spatiotemporal control. We show that the formation of pathologically-relevant inclusions is driven by aberrant interactions between low-complexity domains of TDP-43 that are antagonized by RNA-binding. While stress granules are hypothesized to be a conduit for seeding TDP-43 proteinopathy, we demonstrate pathological inclusions outside these RNA-rich structures. Furthermore, we show that aberrant phase transitions of cytoplasmic TDP-43 are neurotoxic and treatment with oligonucleotides composed of TDP-43 target sequences prevent inclusions and rescue neurotoxicity. Collectively, these studies provide insight into the mechanisms that underlie TDP-43 proteinopathy and present a potential avenue for therapeutic intervention.
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Cites
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Cited by
Biomolecular condensates at the nexus of cellular stress, protein aggregation disease and ageing
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Stress granules and neurodegeneration
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Phase separation and neurodegenerative diseases: a disturbance in the force
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Modulating biomolecular condensates: a novel approach to drug discovery
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Metadata
- Authors
- Mann, J. R., Gleixner, A. M., Mauna, J. C., Gomes, E., DeChellis-Marks, M. R., Needham, P. G., Copley, K. E., Hurtle, B., Portz, B., Pyles, N. J., Guo, L., Calder, C. B., Wills, Z. P., Pandey, U. B., Kofler, J. K., Brodsky, J. L., Thathiah, A., Shorter, J., & Donnelly, C. J.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2019-04
- Volume
- 102
- Issue
- 2
- Pages
- 321-338.e8
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W2917988060
- Cited by
- 537
- References
- 64
- FWCI
- 37.86
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Mann, J. R., Gleixner, A. M., Mauna, J. C., Gomes, E., DeChellis-Marks, M. R., Needham, P. G., Copley, K. E., Hurtle, B., Portz, B., Pyles, N. J., Guo, L., Calder, C. B., Wills, Z. P., Pandey, U. B., Kofler, J. K., Brodsky, J. L., Thathiah, A., Shorter, J., & Donnelly, C. J. (2019). RNA Binding Antagonizes Neurotoxic Phase Transitions of TDP-43. Neuron. https://doi.org/10.1016/j.neuron.2019.01.048
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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