Blood and cerebellar abundance of ATXN3 splice variants in spinocerebellar ataxia type 3/Machado-Joseph disease

Spinocerebellar ataxia type 3 (SCA3)/Machado-Joseph disease (MJD) is a heritable proteinopathy disorder, whose causative gene, ATXN3, undergoes alternative splicing. Ataxin-3 protein isoforms differ in their toxicity, suggesting that certain ATXN3 splice variants may be crucial in driving the selective toxicity in SCA3. Using RNA-seq datasets we identified and determined the abundance of annotated ATXN3 transcripts in blood (n = 60) and cerebellum (n = 12) of SCA3 subjects and controls. The reference transcript (ATXN3–251), translating into an ataxin-3 isoform harbouring three ubiquitin-interacting motifs (UIMs), showed the highest abundance in blood, while the most abundant transcript in the cerebellum (ATXN3–208) was of unclear function. Noteworthy, two of the four transcripts that encode full-length ataxin-3 isoforms but differ in the C-terminus were strongly related with tissue expression specificity: ATXN3–251 (3UIM) was expressed in blood 50-fold more than in the cerebellum, whereas ATXN3–214 (2UIM) was expressed in the cerebellum 20-fold more than in the blood. These findings shed light on ATXN3 alternative splicing, aiding in the comprehension of SCA3 pathogenesis and providing guidance in the design of future ATXN3 mRNA-lowering therapies. •Splice variants of ATXN3, the MJD/SCA3 causative gene, were analyzed in blood and cerebellum samples by RNA-seq.•ATXN3 transcripts diversity and abundance is higher in the cerebellum than in the blood.•The most abundant ATXN3 transcript in the cerebellum is noncoding and of unknown function.•The most abundant ATXN3 transcript in blood is the protein-coding canonical transcript.•2UIM-encoding transcripts are preferentially abundant in the cerebellum, while 3UIM transcripts are frequent in the blood.