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

Journal of Cellular and Molecular Medicine
Guo-Lin ChenGregory M Miller

Abstract

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 ∆E...Continue Reading

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Citations

Mar 3, 2020·Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan·Nozomu Mori
Sep 12, 2019·Scientific Reports·May T Aung-HtutSteve D Wilton
May 8, 2018·Frontiers in Microbiology·Yuchen Nan, Yan-Jin Zhang
Aug 16, 2018·Scientific Reports·Li LuSadhan Majumder
Jan 8, 2020·International Journal of Molecular Sciences·Jose M Garcia-ManteigaJacopo Meldolesi

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Methods Mentioned

BETA
nuclear translocation
Transfection
confocal microscopy
ELISA
PCR
ubiquitination

Software Mentioned

SAS
ImageJ
GeneTools
ImageGauge
Partek ® Genomic Suite

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