A006 Splicing dysregulation is a common theme across Huntington’s disease mouse models and can be rescued by huntingtin lowering

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Huntington’s disease (HD) exhibits a complex molecular phenotype, including significant transcriptional and splicing dysregulation. While splicing dysregulation is known to play a critical role in other repeat expansion disorders such as myotonic dystrophy type 1, its conservation across HD models remains to be fully explored. We investigated splicing dysregulation in various HD mouse models. Publicly available datasets from the NCBI Gene Expression Omnibus (GEO) database were analyzed alongside RNA-sequencing data obtained from YAC128, R6/1 and WT littermates treated with AAVs encoding engineered miRNAs. All data were processed using a custom analysis pipeline. Our findings revealed consistent splicing dysregulation across all assessed HD mouse models, with varying severity. Specifically, the N-terminal R6/1 and R6/2 models exhibited the most pronounced splicing dysregulation, while the Q111 and Q140 knock-in and full-length transgenic BACHD and BAC-CAG models displayed milder effects. Our in-house data correlated well with the other datasets, showing robust splicing dysregulation in 5-month old YAC128 as well as 18-week old R6/1 mice. Importantly, this dysregulation could be partially rescued by treatment with HTT-lowering miRNAs. Altogether, our results suggest that splicing dysregulation is a conserved molecular phenotype in HD mouse models and could serve as a sensitive early marker for evaluating therapeutic efficacy.

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