The DOI matches its Crossref record; 32 of the 32 references it cites were found in a registry or an index.
Structure-based inhibitors of tau aggregation
Open accessAbstract
Aggregated tau protein is associated with over 20 neurological disorders, which include Alzheimer's disease. Previous work has shown that tau's sequence segments VQIINK and VQIVYK drive its aggregation, but inhibitors based on the structure of the VQIVYK segment only partially inhibit full-length tau aggregation and are ineffective at inhibiting seeding by full-length fibrils. Here we show that the VQIINK segment is the more powerful driver of tau aggregation. Two structures of this segment determined by the cryo-electron microscopy method micro-electron diffraction explain its dominant influence on tau aggregation. Of practical significance, the structures lead to the design of inhibitors that not only inhibit tau aggregation but also inhibit the ability of exogenous full-length tau fibrils to seed intracellular tau in HEK293 biosensor cells into amyloid. We also raise the possibility that the two VQIINK structures represent amyloid polymorphs of tau that may account for a subset of prion-like strains of tau. Tau aggregation is associated with Alzheimer's disease and dozens of related dementias. Now atomic structures of the aggregation-prone segment VQIINK in repeat 2 of tau have been reported. Inhibitors designed using these structures block seeding by full-length tau better than inhibitors that target the VQIVYK aggregation segment in repeat 3.
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Cites
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Self-citationCryo-EM structures of tau filaments from Alzheimer’s disease
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Cited by
Nguyen, P. H., Ramamoorthy, A., Sahoo, B. R., Zheng, J., Faller, P., Straub, J. E., Dominguez, L., Shea, J.-E., Dokholyan, N. V., De Simone, A., et al. (2021) · Chemical Reviews · doi:10.1021/acs.chemrev.0c01122 · Cited by 678
Zhang, W., Falcon, B., Murzin, A. G., Fan, J., Crowther, R. A., Goedert, M., & Scheres, S. H. (2019) · eLife · doi:10.7554/elife.43584 · Cited by 499
α-Synuclein misfolding and aggregation: Implications in Parkinson’s disease pathogenesis
Mehra, S., Sahay, S., & Maji, S. K. (2019) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2019.03.001 · Cited by 499
The complexity of tau in Alzheimer’s disease
Naseri, N. N., Wang, H., Guo, J., Sharma, M., & Luo, W. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2019.04.022 · Cited by 373
Rajasekhar, K., & Govindaraju, T. (2018) · RSC Advances · doi:10.1039/c8ra03620a · Cited by 150
Metadata
- Authors
- Seidler, P. M., Boyer, D. R., Rodriguez, J. A., Sawaya, M. R., Cascio, D., Murray, K., Gonen, T., & Eisenberg, D. S.
- Venue
- Nature Chemistry
- Published
- 2017-11-20
- Volume
- 10
- Issue
- 2
- Pages
- 170-176
- ISSN
- 1755-4330 (ISSN-L)
- 1755-4349
- OpenAlex
- W2769171126
- Cited by
- 339
- References
- 32
- FWCI
- 18.71
- Type
- journal article
- Language
- en
- Open access
- green
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- Seidler, P. M., Boyer, D. R., Rodriguez, J. A., Sawaya, M. R., Cascio, D., Murray, K., Gonen, T., & Eisenberg, D. S. (2018). Structure-based inhibitors of tau aggregation. Nature Chemistry. https://doi.org/10.1038/nchem.2889
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