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Updated: Jun 28, 2025
Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
Published on: February 27, 2018
Splice modulators target PMS1 to reduce somatic expansion of the Huntington's disease-associated CAG repeat
Zachariah L McLean1,2,3, Dadi Gao1,2,3, Kevin Correia1
1Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA.
Insights
Small molecules that alter splicing reduce the expansion of toxic gene repeats in Huntington's disease (HD) cells. This suggests PMS1, a gene involved in splicing, is a potential therapeutic target for treating HD.
Area of Science:
- Neurogenetics
- Molecular Biology
- Pharmacology
Background:
- Huntington's disease (HD) is a fatal neurodegenerative disorder.
- It is caused by an expanded CAG repeat in the HTT gene, leading to mutant huntingtin protein.
- Somatic CAG repeat expansion is implicated as a key driver of HD onset.
Purpose of the Study:
- To investigate the effect of splice modulators on unstable HTT exon 1 CAG repeat expansion.
- To identify potential genetic targets for therapeutic intervention in HD.
Main Methods:
- Utilized an engineered cell model with an unstable HTT exon 1 CAG repeat.
- Administered small molecule splice modulators (branaplam and risdiplam).
- Employed CRISPR-Cas9 gene editing to investigate the role of PMS1.
Main Results:
- Branaplam and risdiplam decreased HTT exon 1 CAG repeat expansion.
- This effect was independent of lowering mutant huntingtin levels.
- Pseudoexon inclusion in PMS1 was identified as the mechanism reducing expansion.
- Inactivation of PMS1, particularly homozygous, reduced CAG repeat expansion.
Conclusions:
- PMS1 acts as a genetic modifier of Huntington's disease.
- PMS1 is a potential therapeutic target for HD.
- Splice modulation is a viable strategy, but cell-type specific effects and genetic variations must be considered.
Abstract:
Huntington's disease (HD) is a dominant neurological disorder caused by an expanded HTT exon 1 CAG repeat that lengthens huntingtin's polyglutamine tract. Lowering mutant huntingtin has been proposed for treating HD, but genetic modifiers implicate somatic CAG repeat expansion as the driver of onset. We find that branaplam and risdiplam, small molecule splice modulators that lower huntingtin by promoting HTT pseudoexon inclusion, also decrease expansion of an unstable HTT exon 1 CAG repeat in an engineered cell model. Targeted CRISPR-Cas9 editing shows this effect is not due to huntingtin lowering, pointing instead to pseudoexon inclusion in PMS1. Homozygous but not heterozygous inactivation of PMS1 also reduces CAG repeat expansion, supporting PMS1 as a genetic modifier of HD and a potential target for therapeutic intervention. Although splice modulation provides one strategy, genome-wide transcriptomics also emphasize consideration of cell-type specific effects and polymorphic variation at both target and off-target sites.
