Abstract
Production of protein containing lengthy stretches of polyglutamine encoded by multiple repeats of the trinucleotide CAG is a hallmark of Huntington’s disease (HD) and of a variety of other inherited degenerative neurological and neuromuscular disorders. Earlier work has shown that interference with production of the transcription elongation protein SUPT4H results in decreased cellular capacity to transcribe mutant huntingtin gene (Htt) alleles containing long CAG expansions, but has little effect on expression of genes containing short CAG stretches. zQ175 and R6/2 are genetically engineered mouse strains whose genomes contain human HTT alleles that include greatly expanded CAG repeats and which are used as animal models for HD. Here we show that reduction of SUPT4H expression in brains of zQ175 mice by intracerebroventricular bolus injection of antisense 2’-O-methoxyethyl oligonucleotides (ASOs) directed against Supt4h, or in R6/2 mice by deletion of one copy of the Supt4h gene, results in a decrease in mRNA and protein encoded specifically by mutant Htt alleles. We further show that reduction of SUPT4H in mouse brains is associated with decreased HTT protein aggregation, and in R6/2 mice, also with prolonged lifespan and delay of the motor impairment that normally develops in these animals. Our findings support the view that targeting of SUPT4H function may be useful as a therapeutic countermeasure against HD.
Highlights
Huntington’s disease (HD) is one of a collection of untreatable and devastating neurodegenerative and neuromuscular diseases that result from expansion of segments of trinucleotide repeats (TNRs) present within certain genes [1,2,3]
Our findings indicate that decrease in SUPT4H production in cerebral cortex neurons by injection of antisense oligonucleotides (ASOs) into the brains of mice expressing a human HTT exon containing expanded CAG repeats [14,15] reduces the abundance of mutant huntingtin gene (Htt) mRNA and protein, while having little or no effect on expression of the co-existing normal Htt allele
The anti-sense oligonucleotide (ASO) used was shown in preliminary studies to result in ~80% reduction of Supt4h mRNA in the mouse endothelioma cell line bEnd.3 cells (ATCC CRL-2299)
Summary
Huntington’s disease (HD) is one of a collection of untreatable and devastating neurodegenerative and neuromuscular diseases that result from expansion of segments of trinucleotide repeats (TNRs) present within certain genes [1,2,3]. Whereas the huntingtin (HTT) gene normally includes fewer than 30 repeats of the glutamine-encoding trinucleotide CAG, expansion to 36 or more repeats results in HTT protein containing a long polyglutamine stretch, leading to HTT protein aggregation and non-canonical protein-protein interactions—and resulting in neuronal cell death [4,5,6,7]. Null mutation of spt and reduced transcription through DNA containing lengthy TNRs, can decrease the abundance of and restore functionality to the resulting protein; in mammalian striatal neurons grown in culture, shRNA directed against Supt4h reduces the production, aggregation, and toxicity of mutant HTT protein [13]
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