Effects on murine behavior and lifespan of selectively decreasing expression of mutant huntingtin allele by supt4h knockdown

PLoS Genetics
Hui-Min ChengTzu-Hao Cheng

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 del...Continue Reading

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Citations

Jul 16, 2015·Journal of Neurogenetics·Chia-Rung Liu, Tzu-Hao Cheng
Apr 4, 2017·Current Opinion in Genetics & Development·John Douglas Cleary, Laura Pw Ranum
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Methods Mentioned

BETA
antisense oligonucleotides
antisense oligonucleotide
genotyping
PCR
electrophoresis
X-ray

Software Mentioned

SigmaPlot

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