Mar 3, 2012

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

PLoS Genetics
Monica Banez-CoronelEulàlia Martí

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 acti...Continue Reading

Mentioned in this Paper

MBNL1 gene
Caspase-9
Neuro-Oncological Ventral Antigen 2
Real-Time Polymerase Chain Reaction
Pathogenic Aspects
Northern Blotting
Immunofluorescence Assay
Biochemical Pathway
AGO2 gene
EIF2C3 wt Allele

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