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

• DOI: 10.1016/j.nbd.2024.106456
• Publication Date: 2024-02-27T16:34:42Z
• Authors: Mafalda Raposo; Jeannette Hübener...; Rebecca Tagett; Ana F. Ferreira; Ana Rosa Vieira Melo; João Vasconcelos; Paula Pires; Teresa Kay; Hector Garcia-Moreno; Paola Giunti; Magda M. Santana; Luis Pereira de A...; Jon Infante; Bart P. van de Wa...; Jeroen J. de Vries; Jennifer Faber; Thomas Klockgether; Nicolas Casadei; Jakob Admard; Ludger Schöls; Olaf Riess; Maria do Carmo Costa; Manuela Lima
• Keywords: 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 driving the selective toxicity SCA3. Using RNA-seq datasets we identified and determined abundance of annotated transcripts blood (n = 60) cerebellum 12) SCA3 subjects controls. The reference transcript (ATXN3–251), translating into an ataxin-3 isoform harbouring three ubiquitin-interacting motifs (UIMs), showed highest blood, while most abundant (ATXN3–208) was unclear function. Noteworthy, two four encode full-length but C-terminus were strongly related with tissue expression specificity: ATXN3–251 (3UIM) expressed 50-fold more than cerebellum, whereas ATXN3–214 (2UIM) 20-fold blood. These findings shed light on splicing, aiding comprehension pathogenesis providing guidance design future mRNA-lowering therapies.