Abstract：
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.
摘要：
脊髓小脑性共济失调3型（SCA3）/Machado-Joseph病（MJD）是一种遗传性蛋白质病，谁的致病基因，ATXN3经历选择性剪接。Ataxin-3蛋白亚型的毒性不同，提示某些ATXN3剪接变体可能在驱动SCA3的选择性毒性方面至关重要。使用RNA-seq数据集，我们鉴定并确定了SCA3受试者和对照的血液（n=60）和小脑（n=12）中注释的ATXN3转录本的丰度。参考转录本（ATXN3-251），翻译成含有三个泛素相互作用基序（UIM）的共济失调蛋白3同工型，显示血液中最高的丰度，而小脑中最丰富的转录本（ATXN3-208）功能不清楚。值得注意的是,编码全长ataxin-3同工型但C末端不同的四种转录本中的两种与组织表达特异性密切相关：ATXN3-251（3UIM）在血液中的表达比小脑高50倍，而ATXN3-214（2UIM）在小脑中的表达比在血液中的表达高20倍。这些发现揭示了ATXN3选择性剪接，有助于理解SCA3的发病机制，并为设计未来的ATXN3mRNA降低疗法提供指导。
