Dr. Harry Orr

Lab Medicine & Pathology
Medical School
Twin Cities
Project Title: 
Neural Degenerative Disease-Caused Spinocerabellar Ataxia 1

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. Over the next year new genetic mouse models will be sent for RNA-seq and need to be analyzed and compared to the existing datasets. This will continue to refine the researchers' understanding of SCA-1. Specifically, they have created four mouse models that remove Ataxin1, via CRE recombination, from specific cell types. Changing the expression pattern of Ataxin 1 in various areas of the brain will have a profound effect RNA expression and ultimately disease phenotype.

MSI resources are used for data storage and analysis for this project, and RIS personnel provide bioinformatic analysis and support.

This group's research was featured on the MSI website in December 2020: Spinocerebellar Ataxia.

Project Investigators

Lisa Duvick
Dr. Hillary Handler
Dr. Christy Henzler
Brennon O'Callaghan
Dr. Harry Orr
Orion Rainwater
Praseuth Yang
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