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Reduction of Huntington’s Disease RNA Foci by CAG Repeat-Targeting Reagents

In several human polyglutamine diseases caused by expansions of CAG repeats in the coding sequence of single genes, mutant transcripts are detained in nuclear RNA foci. In polyglutamine disorders, unlike other repeat-associated diseases, both RNA and proteins exert pathogenic effects; therefore, dec...

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Autores principales: Urbanek, Martyna O., Fiszer, Agnieszka, Krzyzosiak, Wlodzimierz J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5368221/
https://www.ncbi.nlm.nih.gov/pubmed/28400719
http://dx.doi.org/10.3389/fncel.2017.00082
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author Urbanek, Martyna O.
Fiszer, Agnieszka
Krzyzosiak, Wlodzimierz J.
author_facet Urbanek, Martyna O.
Fiszer, Agnieszka
Krzyzosiak, Wlodzimierz J.
author_sort Urbanek, Martyna O.
collection PubMed
description In several human polyglutamine diseases caused by expansions of CAG repeats in the coding sequence of single genes, mutant transcripts are detained in nuclear RNA foci. In polyglutamine disorders, unlike other repeat-associated diseases, both RNA and proteins exert pathogenic effects; therefore, decreases of both RNA and protein toxicity need to be addressed in proposed treatments. A variety of oligonucleotide-based therapeutic approaches have been developed for polyglutamine diseases, but concomitant assays for RNA foci reduction are lacking. Here, we show that various types of oligonucleotide-based reagents affect RNA foci number in Huntington’s disease cells. We analyzed the effects of reagents targeting either CAG repeat tracts or specific HTT sequences in fibroblasts derived from patients. We tested reagents that either acted as translation blockers or triggered mRNA degradation via the RNA interference pathway or RNase H activation. We also analyzed the effect of chemical modifications of CAG repeat-targeting siRNAs on their efficiency in the foci decline. Our results suggest that the decrease of RNA foci number may be considered as a readout of treatment outcomes for oligonucleotide reagents.
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spelling pubmed-53682212017-04-11 Reduction of Huntington’s Disease RNA Foci by CAG Repeat-Targeting Reagents Urbanek, Martyna O. Fiszer, Agnieszka Krzyzosiak, Wlodzimierz J. Front Cell Neurosci Neuroscience In several human polyglutamine diseases caused by expansions of CAG repeats in the coding sequence of single genes, mutant transcripts are detained in nuclear RNA foci. In polyglutamine disorders, unlike other repeat-associated diseases, both RNA and proteins exert pathogenic effects; therefore, decreases of both RNA and protein toxicity need to be addressed in proposed treatments. A variety of oligonucleotide-based therapeutic approaches have been developed for polyglutamine diseases, but concomitant assays for RNA foci reduction are lacking. Here, we show that various types of oligonucleotide-based reagents affect RNA foci number in Huntington’s disease cells. We analyzed the effects of reagents targeting either CAG repeat tracts or specific HTT sequences in fibroblasts derived from patients. We tested reagents that either acted as translation blockers or triggered mRNA degradation via the RNA interference pathway or RNase H activation. We also analyzed the effect of chemical modifications of CAG repeat-targeting siRNAs on their efficiency in the foci decline. Our results suggest that the decrease of RNA foci number may be considered as a readout of treatment outcomes for oligonucleotide reagents. Frontiers Media S.A. 2017-03-28 /pmc/articles/PMC5368221/ /pubmed/28400719 http://dx.doi.org/10.3389/fncel.2017.00082 Text en Copyright © 2017 Urbanek, Fiszer and Krzyzosiak. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Urbanek, Martyna O.
Fiszer, Agnieszka
Krzyzosiak, Wlodzimierz J.
Reduction of Huntington’s Disease RNA Foci by CAG Repeat-Targeting Reagents
title Reduction of Huntington’s Disease RNA Foci by CAG Repeat-Targeting Reagents
title_full Reduction of Huntington’s Disease RNA Foci by CAG Repeat-Targeting Reagents
title_fullStr Reduction of Huntington’s Disease RNA Foci by CAG Repeat-Targeting Reagents
title_full_unstemmed Reduction of Huntington’s Disease RNA Foci by CAG Repeat-Targeting Reagents
title_short Reduction of Huntington’s Disease RNA Foci by CAG Repeat-Targeting Reagents
title_sort reduction of huntington’s disease rna foci by cag repeat-targeting reagents
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5368221/
https://www.ncbi.nlm.nih.gov/pubmed/28400719
http://dx.doi.org/10.3389/fncel.2017.00082
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