Region-specific pathogenic transcriptome profiles – Towards understanding regional variation in SCA1 pathogenesis

Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited ataxia caused by expansion of a translated unstable CAG repeat encoding a glutamine tract in the Ataxin-1 (ATXN1) protein. We investigated the therapeutic capability of an antisense oligonucleotide (ASO) targeting mouse Atxn1 in Atxn1^154Q/2Q knockin mice that manifest motor deficits and premature lethality. Following a single ASO treatment at 5 weeks of age, mice demonstrated rescue of these disease-associated phenotypes. RNA-seq analysis of genes whose expression was restored to WT levels in ASO-treated Atxn1^154Q/2Q mice was used to demonstrate molecular differences between SCA1 pathogenesis in the cerebellum with disease in the medulla. This work provides proof-of-concept for the ability of an ATXN1 targeting ASO to rescue two seminal SCA1 phenotypes: ataxia and premature lethality. In addition, analyses of RNA-seq data indicates that regional differences in disease processes between the cerebellum and medulla exist such that a therapy designed to target a pathogenic pathway active in one region is unlikely to substantially impact disease in other brain regions affected by SCA1. These findings further support the therapeutic value of an approach such as ASO-mediated reduction of ATXN1 RNA, which is effective across multiple regions of the brain and their corresponding cellular pathways affected by SCA1.