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

Abstract

ABSTRACTBackgroundSpinocerebellar 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 specificATXN3splice variants play key roles in promoting the selective toxicity displayed in SCA3/MJD.MethodsUsing RNA-seq datasets we identified and determined the abundance of annotatedATXN3transcripts in blood (n=60) and cerebellum (n=12) of SCA3/MJD subjects and controls.ResultsGlobally, the number and the abundance of individualATXN3transcripts 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 ofATXN3-251 andATXN3-214, 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, whereasATXN3-214 (2UIM) was expressed in the cerebellum 20-fold more than in blood.ConclusionsThese findings provide new insights into the elucidation ofATXN3AS in different tissues, contributing for a better understanding of SCA3/MJD pathogenesis and providing information for the development of future effectiveATXN3mRNA-lowering therapies.