title: A pathogenic mechanism in Huntington's disease involves small CAG-repeated RNAs with neurotoxic activity.
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.
authors.affiliation: Genes and Disease Programme, Centre for Genomic Regulation and Universitat Pompeu Fabra, Barcelona, Catalonia, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: Bañez-Coronel
authors.forename: Silvia
authors.initials: S
authors.lastname: Porta
authors.forename: Birgit
authors.initials: B
authors.lastname: Kagerbauer
authors.forename: Elisabet
authors.initials: E
authors.lastname: Mateu-Huertas
authors.forename: Lorena
authors.initials: L
authors.lastname: Pantano
authors.forename: Isidre
authors.initials: I
authors.lastname: Ferrer
authors.forename: Manuel
authors.initials: M
authors.lastname: Guzmán
authors.forename: Xavier
authors.initials: X
authors.lastname: Estivill
authors.forename: Eulàlia
authors.initials: E
authors.lastname: Martí
mesh_terms: D005091:Exons; D020868:Gene Silencing; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D019680:Trinucleotide Repeat Expansion
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D010455:Peptides; D012333:RNA, Messenger; C097188:polyglutamine