The DOI matches its Crossref record; 44 of the 44 references it cites were found in a registry or an index.
Aggregated polyglutamine peptides delivered to nuclei are toxic to mammalian cells
Abstract
A number of observations point to the aggregation of expanded polyglutamine [poly(Q)]-containing proteins as playing a central role in the etiology of Huntington's disease (HD) and other expanded CAG-repeat diseases. Transfected cell and transgenic animal models provide some of this support, but irrefutable data on the cytotoxicity of poly(Q) aggregates is lacking. This may be due in part to difficulties in observing all aggregated states in these models, and in part to the inability to conclusively rule out the role of monomeric states of the poly(Q) protein. To address these questions, we produced aggregates of simple poly(Q) peptides in vitro and introduced them to mammalian cells in culture. We find that Cos-7 and PC-12 cells in culture readily take up aggregates of chemically synthesized poly(Q) peptides. Simple poly(Q) aggregates are localized to the cytoplasm and have little impact on cell viability. Aggregates of poly(Q) peptides containing a nuclear localization signal, however, are localized to nuclei and lead to dramatic cell death. Amyloid fibrils of a non-poly(Q) peptide are non-toxic, whether localized to the cytoplasm or nucleus. Nuclear localization of an aggregate of a short, Q(20), poly(Q) peptide is just as toxic as that of a long poly(Q) peptide, supporting the notion that the influence of poly(Q) repeat length on disease risk and age of onset is at the level of aggregation efficiency. The results support a direct role for poly(Q) aggregates in HD-related neurotoxicity.
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Citations
Cites
Aggregation of Huntingtin in Neuronal Intranuclear Inclusions and Dystrophic Neurites in Brain
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Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases
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Glutamine Repeats and Neurodegeneration
Zoghbi, H. Y., & Orr, H. T. (2000) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.23.1.217 · Cited by 1,309
Scherzinger, E., Lurz, R., Turmaine, M., Mangiarini, L., Hollenbach, B., Hasenbank, R., Bates, G. P., Davies, S. W., Lehrach, H., & Wanker, E. E. (1997) · Cell · doi:10.1016/s0092-8674(00)80514-0 · Cited by 1,291 · cited 1×
“11, No. 23 2905–2917 sequences form aggregates (4,5, 14 ,15).”
Amyloid pores from pathogenic mutations
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Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila
Steffan, J. S., Bodai, L., Pallos, J., Poelman, M., McCampbell, A., Apostol, B. L., Kazantsev, A., Schmidt, E., Zhu, Y.-Z., Greenwald, M., et al. (2001) · Nature · doi:10.1038/35099568 · Cited by 1,228 · cited 1×
“The importance of the poly(Q) sequence for cytotoxicity, relative to other sequence elements in expanded CAG-repeat disease proteins, is also not always clear ( 24 ).”
BackgroundNucifora, F. C., Sasaki, M., Peters, M. F., Huang, H., Cooper, J. K., Yamada, M., Takahashi, H., Tsuji, S., Troncoso, J., Dawson, V. L., et al. (2001) · Science · doi:10.1126/science.1056784 · Cited by 1,094
Ataxin-1 Nuclear Localization and Aggregation
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Cited by
Bates, G. P., Dorsey, R., Gusella, J. F., Hayden, M. R., Kay, C., Leavitt, B. R., Nance, M., Ross, C. A., Scahill, R. I., Wetzel, R., et al. (2015) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2015.5 · Cited by 1,641
Propagation of Tau Misfolding from the Outside to the Inside of a Cell
Frost, B., Jacks, R. L., & Diamond, M. I. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m808759200 · Cited by 1,252
Molecular Mechanisms and Potential Therapeutical Targets in Huntington's Disease
Zuccato, C., Valenza, M., & Cattaneo, E. (2010) · Physiological Reviews · doi:10.1152/physrev.00041.2009 · Cited by 848
Prion-like transmission of protein aggregates in neurodegenerative diseases
Brundin, P., Melki, R., & Kopito, R. (2010) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2873 · Cited by 778
Prion-like mechanisms in neurodegenerative diseases
Frost, B., & Diamond, M. I. (2010) · Nature Reviews Neuroscience · doi:10.1038/nrn2786 · Cited by 776
Metadata
- Authors
- Yang, W.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2002-11-01
- Volume
- 11
- Issue
- 23
- Pages
- 2905-2917
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2141583055
- Cited by
- 371
- References
- 44
- FWCI
- 7.95
- Type
- journal article
- Language
- en
- Open access
- closed
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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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