Blood and cerebellar abundance ofATXN3splice variants in spinocerebellar ataxia type 3/Machado-Joseph disease

ABSTRACT Background Spinocerebellar ataxia type 3 (SCA3)/Machado-Joseph disease (MJD) is an autosomal dominant polyglutamine disease. SCA3/MJD causative gene, ATXN3 , is known to undergo alternative splicing (AS) and 54 transcripts are currently annotated. Differences in the toxicity of ataxin-3 protein isoforms, harbouring on its C-terminus two or three ubiquitin interacting motifs (UIMs), were previously uncovered, raising the hypothesis that specific ATXN3 splice variants play key roles in promoting the selective toxicity displayed in SCA3/MJD. Methods Using RNA-seq datasets we identified and determined the abundance of annotated ATXN3 transcripts in blood (n=60) and cerebellum (n=12) of SCA3/MJD subjects and controls. Results Globally, the number and the abundance of individual ATXN3 transcripts were higher in the cerebellum than in the blood. While the most abundant transcript in the cerebellum was a protein with a coding sequence not defined of unknown function ( ATXN3 -208), the transcript with the highest abundance in blood was the reference transcript ( ATXN3 -251) which translates into an ataxin-3 isoform harboring three UIMs. Noteworthy, the abundance of ATXN3 -251 and ATXN3 -214, two out of the four transcripts that encode full-length ataxin-3 protein 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 cerebellum, whereas ATXN3 -214 (2UIM) was expressed in the cerebellum 20-fold more than in blood. Conclusions These findings provide new insights into the elucidation of ATXN3 AS in different tissues, contributing for a better understanding of SCA3/MJD pathogenesis and providing information for the development of future effective ATXN3 mRNA-lowering therapies.