Spinocerebellar Ataxia type 1 (SCA-1) disease is caused by the expansion of a CAG repeat that encodes a polyglutamine tract in Ataxin-1. Previous studies demonstrated a gain-of-function mechanism underlies this disease. The glutamine expansion alters its interactions with capicua and RBM17, regulators of RNA transcription and splicing respectively. Successful RNA-seq projects have identified significant changes in RNA transcription and splicing patterns between healthy and diseased mice. This group has demonstrated the ability to deliver an artificial oligonucleotide that knocks down Ataxin-1 RNA levels, concomitantly reducing protein levels, significantly reducing the disease phenotype.
The researchers will use this information to continue their search for influenced pathways and to identify transcriptional regulatory sequences. They will also pursue tissue specific mapping of changes. New Cre expressing mouse models will be crossed to Ataxin-1 disease mice. RNA-seq will be used to explore different tissues within these mice. RNA-seq is the starting point to analyze and compare to the previous datasets. Changing the expression pattern of Ataxin 1 in various areas of the brain has had profound effects on RNA expression and ultimately disease phenotype.
MSI resources are used for data storage and analysis for this project, and MSI Bioinformatics personnel provide bioinformatic analysis and support.
This group's research was featured on the MSI website in December 2020: Spinocerebellar Ataxia.