The DOI matches its Crossref record; 9 of the 9 references it cites were found in a registry or an index.
A Pathogenic Mechanism in Huntington's Disease Involves Small CAG-Repeated RNAs with Neurotoxic Activity
Open accessAbstract
Huntington's disease (HD) is an autosomal dominantly inherited disorder caused by the expansion of CAG repeats in the Huntingtin (HTT) gene. The abnormally extended polyglutamine in the HTT protein encoded by the CAG repeats has toxic effects. Here, we provide evidence to support that the mutant HTT CAG repeats interfere with cell viability at the RNA level. In human neuronal cells, expanded HTT exon-1 mRNA with CAG repeat lengths above the threshold for complete penetrance (40 or greater) induced cell death and increased levels of small CAG-repeated RNAs (sCAGs), of ≈21 nucleotides in a Dicer-dependent manner. The severity of the toxic effect of HTT mRNA and sCAG generation correlated with CAG expansion length. Small RNAs obtained from cells expressing mutant HTT and from HD human brains significantly decreased neuronal viability, in an Ago2-dependent mechanism. In both cases, the use of anti-miRs specific for sCAGs efficiently blocked the toxic effect, supporting a key role of sCAGs in HTT-mediated toxicity. Luciferase-reporter assays showed that expanded HTT silences the expression of CTG-containing genes that are down-regulated in HD. These results suggest a possible link between HD and sCAG expression with an aberrant activation of the siRNA/miRNA gene silencing machinery, which may trigger a detrimental response. The identification of the specific cellular processes affected by sCAGs may provide insights into the pathogenic mechanisms underlying HD, offering opportunities to develop new therapeutic approaches.
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Cites
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Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death
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Trinucleotide repeat length instability and age of onset in Huntington's disease
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Cited by
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Jimenez-Sanchez, M., Licitra, F., Underwood, B. R., & Rubinsztein, D. C. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a024240 · Cited by 507
Double-Stranded RNA Sensors and Modulators in Innate Immunity
Hur, S. (2019) · Annual Review of Immunology · doi:10.1146/annurev-immunol-042718-041356 · Cited by 420
Evidence for the biogenesis of more than 1,000 novel human microRNAs
Friedländer, M. R., Lizano, E., Houben, A. J., Bezdan, D., Báñez-Coronel, M., Kudla, G., Mateu-Huertas, E., Kagerbauer, B., González, J., Chen, K. C., et al. (2014) · Genome Biology · doi:10.1186/gb-2014-15-4-r57 · Cited by 256
Self-citationFunctional roles and networks of non-coding RNAs in the pathogenesis of neurodegenerative diseases
Wu, Y.-Y., & Kuo, H.-C. (2020) · Journal of Biomedical Science · doi:10.1186/s12929-020-00636-z · Cited by 213
Noncoding RNAs in neurodegeneration
Salta, E., & De Strooper, B. (2017) · Nature Reviews Neuroscience · doi:10.1038/nrn.2017.90 · Cited by 183
Metadata
- Authors
- Bañez-Coronel, M., Porta, S., Kagerbauer, B., Mateu-Huertas, E., Pantano, L., Ferrer, I., Guzmán, M., Estivill, X., & Martí, E.
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-02-23
- Volume
- 8
- Issue
- 2
- Pages
- e1002481
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- OpenAlex
- W1980624807
- Cited by
- 188
- References
- 9
- FWCI
- 5.04
- Type
- journal article
- Language
- en
- Open access
- gold
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- Bañez-Coronel, M., Porta, S., Kagerbauer, B., Mateu-Huertas, E., Pantano, L., Ferrer, I., Guzmán, M., Estivill, X., & Martí, E. (2012). A Pathogenic Mechanism in Huntington's Disease Involves Small CAG-Repeated RNAs with Neurotoxic Activity. PLoS Genetics. https://doi.org/10.1371/journal.pgen.1002481
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