RNA Therapeutics Institute Publications

UMMS Affiliation

RNA Therapeutics Institute; Department of Neurology; Department of Medicine; Program in Molecular Medicine; Graduate School of Biomedical Sciences

Publication Date

2018-09-04

Document Type

Article

Disciplines

Cell and Developmental Biology | Cells | Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Genetic Phenomena | Genetics and Genomics | Nervous System Diseases | Neuroscience and Neurobiology | Nucleic Acids, Nucleotides, and Nucleosides

Abstract

Huntington's disease (HD) is a monogenic neurodegenerative disorder representing an ideal candidate for gene silencing with oligonucleotide therapeutics (i.e., antisense oligonucleotides [ASOs] and small interfering RNAs [siRNAs]). Using an ultra-sensitive branched fluorescence in situ hybridization (FISH) method, we show that approximately 50% of wild-type HTT mRNA localizes to the nucleus and that its nuclear localization is observed only in neuronal cells. In mouse brain sections, we detect Htt mRNA predominantly in neurons, with a wide range of Htt foci observed per cell. We further show that siRNAs and ASOs efficiently eliminate cytoplasmic HTT mRNA and HTT protein, but only ASOs induce a partial but significant reduction of nuclear HTT mRNA. We speculate that, like other mRNAs, HTT mRNA subcellular localization might play a role in important neuronal regulatory mechanisms.

Keywords

ASOs, CAG repeat RNA foci, HTT mRNA, Huntington’s disease, RNA fluorescence in situ hybridization, confocal microscopy, siRNAs

Rights and Permissions

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

DOI of Published Version

10.1016/j.celrep.2018.07.106

Source

Cell Rep. 2018 Sep 4;24(10):2553-2560.e5. doi: 10.1016/j.celrep.2018.07.106. Link to article on publisher's site

Journal/Book/Conference Title

Cell reports

Related Resources

Link to Article in PubMed

PubMed ID

30184490

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

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