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J Cell Mol Med. 2017 Nov;21(11):2974-2984. doi: 10.1111/jcmm.13209. Epub 2017 May 19.

Modulation of nuclear REST by alternative splicing: a potential therapeutic target for Huntington's disease.

Chen GL1,2,3, Ma Q4, Goswami D5,6,7, Shang J1, Miller GM1,8.

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Department of Pharmaceutical Sciences and Center for Drug Discovery, School of Pharmacy, Northeastern University, Boston, MA, USA.
Guangxi Collaborative Innovation Center for Biomedicine, Guangxi Medical University, Nanning, Guangxi, China.
Research Center for Regenerative Medicine of Guangxi, Guangxi Medical University, Nanning, Guangxi, China.
Department of Psychiatry, Institute for Human Performance, SUNY Upstate Medical University, Syracuse, NY, USA.
Center for the Study of Traumatic Encephalopathy, Boston University School of Medicine, Boston, MA, USA.
Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
VA Boston HealthCare System, Boston, MA, USA.
Department of Chemical Engineering, School of Engineering, Northeastern University, Boston, MA, USA.


Huntington's disease (HD) is caused by a genetically mutated huntingtin (mHtt) protein with expanded polyQ stretch, which impairs cytosolic sequestration of the repressor element-1 silencing transcription factor (REST), resulting in excessive nuclear REST and subsequent repression of neuronal genes. We recently demonstrated that REST undergoes extensive, context-dependent alternative splicing, of which exon-3 skipping (∆E3 )-a common event in human and nonhuman primates-causes loss of a motif critical for REST nuclear targeting. This study aimed to determine whether ∆E3 can be targeted to reduce nuclear REST and rescue neuronal gene expression in mouse striatal-derived, mHtt-expressing STHdhQ111/Q111 cells-a well-established cellular model of HD. We designed two morpholino antisense oligos (ASOs) targeting the splice sites of Rest E3 and examined their effects on ∆E3 , nuclear Rest accumulation and Rest-controlled gene expression in STHdhQ111/Q111 cells. We found that (1) the ASOs treatment significantly induced ∆E3 , reduced nuclear Rest, and rescued transcription and/or mis-splicing of specific neuronal genes (e.g. Syn1 and Stmn2) in STHdhQ111/Q111 cells; and (2) the ASOs-induced transcriptional regulation was dependent on ∆E3 induction and mimicked by siRNA-mediated knock-down of Rest expression. Our findings demonstrate modulation of nuclear REST by ∆E3 and its potential as a new therapeutic target for HD and provide new insights into environmental regulation of genome function and pathogenesis of HD. As ∆E3 is modulated by cellular signalling and linked to various types of cancer, we anticipate that ∆E3 contributes to environmentally tuned REST function and may have a broad range of clinical implications.


Huntington's disease; PPARγ; REST/NRSF; Stmn2; Syn-1; alternative splicing; antisense oligos; gene therapy; nuclear translocation

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