Nuclear Localization of Huntingtin mRNA Is Specific to Cells of Neuronal Origin

被引：41

作者：

Didiot, Marie-Cecile ^{[1
]}

Ferguson, Chantal M. ^{[1
]}

Ly, Socheata ^{[1
]}

Coles, Andrew H. ^{[1
]}

Smith, Abigail O. ^{[1
]}

Bicknell, Alicia A. ^{[1
]}

Hall, Lauren M. ^{[1
]}

Sapp, Ellen ^{[3
]}

Echeverria, Dimas ^{[1
]}

Pai, Athma A. ^{[1
]}

DiFiglia, Marian ^{[3
]}

Moore, Melissa J. ^{[1
,6
]}

Hayward, Lawrence J. ^{[4
]}

Aronin, Neil ^{[1
,5
]}

Khvorova, Anastasia ^{[1
,2
]}

机构：

[1] Univ Massachusetts, RNA Therapeut Inst, Med Sch, Worcester, MA 01605 USA

[2] Univ Massachusetts, Med Sch, Program Mol Med, Worcester, MA 01605 USA

[3] Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Charlestown, MA 02129 USA

[4] Univ Massachusetts, Dept Neurol, Med Sch, Worcester, MA 01605 USA

[5] Univ Massachusetts, Dept Med, Med Sch, Worcester, MA 01605 USA

[6] Moderna Therapeut, 200 Technol Sq, Cambridge, MA 02139 USA

来源：

CELL REPORTS | 2018年 / 24卷 / 10期

关键词：

HUMAN FIBROBLASTS; DISEASE GENE; BRAIN; IMAGE; FOCI;

D O I：

10.1016/j.celrep.2018.07.106

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 similar to 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.

引用

页码：2553 / +

页数：13

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