Project Abstract Microsatellite repeat expansions are a growing family of 50+ neurological, neuromuscular, and neurodegenerative diseases that includes the most common cause of adult-onset muscular dystrophy (myotonic dystrophy, DM) and large group of rare neurodegenerative diseases spinocerebellar ataxias, SCAs). There are more than 40 genetically heterogeneous rare SCAs, with the most common forms associated with CAG repeat expansion mutations. Expression of these repeats leads to translation into toxic polyglutamine expansion proteins whose pathogenic role is not well understood. The Berglund and Shorrock groups have preliminary data that supports alternative splicing as a novel CAG-dependent transcriptomic hallmark of SCAs and that targeting CAG repeat expansions with small molecules could provide therapeutic potential across multiple SCAs. The focus of this supplement for Caroline Pritchard is a parallel study that seeks to draw potential overlaps in the transcriptomic dysregulation in CAG SCAs and another repeat expansion disease, myotonic dystrophy type 1 (DM1). In contrast to the SCAs, the mechanism of disease pathogenesis for DM1 is well studied and involves the expression of CUG expansion RNAs that sequester RNA binding proteins, leading to alternative splicing dysregulation and a “spliceopathy”. This project, which supports the research and career training of Caroline Pritchard, will focus on bioinformatic approaches to characterize the interface between these repeat expansion disorders. The overlap in transcriptomic dysregulation between brains affected by CAG SCAs and CUG DM1 is expected to reveal underlying common disease pathomechanisms, which will complement the parent grant’s focus on CAG SCA disease mechanisms. Furthermore, the project will explore if splicing dysregulation associated with repeat expansion diseases is coordinated at the transcript level by long-read sequencing technologies. By characterizing parallel alternative splicing disease mechanisms in multiple repeat expansion disease and the synergy in splicing dysregulation at the transcript level will not only enhance our understanding of the disease biology of SCAs but also open up new potential avenues for therapeutic development across the entire family of repeat expansion diseases.