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

Huntington's disease ( HD ) is caused by a genetically mutated huntingtin ( mH tt) 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 (∆E 3 )—a common event in human and nonhuman primates—causes loss of a motif critical for REST nuclear targeting. This study aimed to determine whether ∆E 3 can be targeted to reduce nuclear REST and rescue neuronal gene expression in mouse striatal‐derived, mH tt‐expressing STH dh Q111/Q111 cells—a well‐established cellular model of HD . We designed two morpholino antisense oligos ( ASO s) targeting the splice sites of Rest E 3 and examined their effects on ∆E 3 , nuclear Rest accumulation and Rest‐controlled gene expression in STH dh Q111/Q111 cells. We found that (1) the ASO s treatment significantly induced ∆E 3 , reduced nuclear Rest, and rescued transcription and/or mis‐splicing of specific neuronal genes ( e.g. Syn1 and Stmn2 ) in STH dh Q111/Q111 cells; and (2) the ASO s‐induced transcriptional regulation was dependent on ∆E 3 induction and mimicked by si RNA ‐mediated knock‐down of Rest expression. Our findings demonstrate modulation of nuclear REST by ∆E 3 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 ∆E 3 is modulated by cellular signalling and linked to various types of cancer, we anticipate that ∆E 3 contributes to environmentally tuned REST function and may have a broad range of clinical implications.