RNA Therapeutics Institute; Department of Neurology; Department of Medicine; Program in Molecular Medicine; Graduate School of Biomedical Sciences
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
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.
ASOs, CAG repeat RNA foci, HTT mRNA, Huntington’s disease, RNA fluorescence in situ hybridization, confocal microscopy, siRNAs
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DOI of Published Version
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
Didiot, Marie C.; Ferguson, Chantal M.; Ly, Socheata; Coles, Andrew H.; Smith, Abigail O.; Bicknell, Alicia A.; Hall, Lauren M.; Sapp, Ellen; Echeverria, Dimas; Pai, Athma A.; DiFiglia, Marian; Moore, Melissa J.; Hayward, Lawrence J.; Aronin, Neil; and Khvorova, Anastasia, "Nuclear Localization of Huntingtin mRNA Is Specific to Cells of Neuronal Origin" (2018). RNA Therapeutics Institute Publications. 41.
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This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
Cell and Developmental Biology Commons, Cells Commons, Congenital, Hereditary, and Neonatal Diseases and Abnormalities Commons, Genetic Phenomena Commons, Genetics and Genomics Commons, Nervous System Diseases Commons, Neuroscience and Neurobiology Commons, Nucleic Acids, Nucleotides, and Nucleosides Commons