A pathogenic mechanism in huntington's disease involves small CAG-repeated RNAs with neurotoxic activity

Mónica Bañez-Coronel, Silvia Porta, Birgit Kagerbauer, Elisabet Mateu-Huertas, Lorena Pantano, Isidre Ferrer, Manuel Guzmán, Xavier P. Estivill, Eulàlia Martí

Research output: Contribution to journalArticle

96 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbere1002481
JournalPLoS Genetics
Volume8
Issue number2
DOIs
Publication statusPublished - Feb 2012
Externally publishedYes

Fingerprint

Huntington Disease
RNA
Poisons
gene
penetrance
mutants
viability
genetic disorders
gene silencing
luciferase
small interfering RNA
microRNA
human diseases
exons
cell viability
cell death
genes
neurons
nucleotides
Messenger RNA

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Bañez-Coronel, M., Porta, S., Kagerbauer, B., Mateu-Huertas, E., Pantano, L., Ferrer, I., ... Martí, E. (2012). A pathogenic mechanism in huntington's disease involves small CAG-repeated RNAs with neurotoxic activity. PLoS Genetics, 8(2), [e1002481]. https://doi.org/10.1371/journal.pgen.1002481

A pathogenic mechanism in huntington's disease involves small CAG-repeated RNAs with neurotoxic activity. / Bañez-Coronel, Mónica; Porta, Silvia; Kagerbauer, Birgit; Mateu-Huertas, Elisabet; Pantano, Lorena; Ferrer, Isidre; Guzmán, Manuel; Estivill, Xavier P.; Martí, Eulàlia.

In: PLoS Genetics, Vol. 8, No. 2, e1002481, 02.2012.

Research output: Contribution to journalArticle

Bañez-Coronel, M, Porta, S, Kagerbauer, B, Mateu-Huertas, E, Pantano, L, Ferrer, I, Guzmán, M, Estivill, XP & Martí, E 2012, 'A pathogenic mechanism in huntington's disease involves small CAG-repeated RNAs with neurotoxic activity', PLoS Genetics, vol. 8, no. 2, e1002481. https://doi.org/10.1371/journal.pgen.1002481
Bañez-Coronel M, Porta S, Kagerbauer B, Mateu-Huertas E, Pantano L, Ferrer I et al. A pathogenic mechanism in huntington's disease involves small CAG-repeated RNAs with neurotoxic activity. PLoS Genetics. 2012 Feb;8(2). e1002481. https://doi.org/10.1371/journal.pgen.1002481
Bañez-Coronel, Mónica ; Porta, Silvia ; Kagerbauer, Birgit ; Mateu-Huertas, Elisabet ; Pantano, Lorena ; Ferrer, Isidre ; Guzmán, Manuel ; Estivill, Xavier P. ; Martí, Eulàlia. / A pathogenic mechanism in huntington's disease involves small CAG-repeated RNAs with neurotoxic activity. In: PLoS Genetics. 2012 ; Vol. 8, No. 2.
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