Please use this identifier to cite or link to this item: http://hdl.handle.net/2445/49112
Title: A pathogenic mechanism in Huntington"s disease involves small CAG-repeated RNAs with neurotoxic activity
Author: Bañez-Coronel, M.
Porta, Silvia
Kagerbauer, Birgit
Mateu Huertas, Elisabet
Pantano, Lorena
Ferrer, Isidro (Ferrer Abizanda)
Guzmán, Manuel
Estivill, Xavier, 1955-
Martí, Eulàlia
Keywords: Corea de Huntington
Pèptids
Teixit nerviós
Neurotoxines
Huntington's chorea
Peptides
Nerve tissue
Neurotoxins
Issue Date: 23-Feb-2012
Publisher: Public Library of Science (PLoS)
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
Note: Reproducció del document publicat a: http://dx.doi.org/10.1371/journal.pgen.1002481
It is part of: PLoS Genetics, 2012, vol. 8, num. 2, p. 1-15
Related resource: http://dx.doi.org/10.1371/journal.pgen.1002481
URI: http://hdl.handle.net/2445/49112
ISSN: 1553-7390
Appears in Collections:Articles publicats en revistes (Patologia i Terapèutica Experimental)

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