Differential toxicity of ataxin-3 isoforms in Drosophila models of Spinocerebellar Ataxia Type 3

摘要: Abstract The most commonly inherited dominant ataxia, Spinocerebellar Ataxia Type 3 (SCA3), is caused by a CAG repeat expansion that encodes an abnormally long polyglutamine (polyQ) in the disease protein ataxin-3, deubiquitinase. Two major full-length isoforms of ataxin-3 exist, both which contain same N-terminal portion and polyQ repeat, but differ their C-termini; one (denoted here as isoform 1) contains motif binds ataxin-3's substrate, ubiquitin, whereas other 2) has hydrophobic tail. Most SCA3 studies have focused on 1, predominant version mammalian brain, yet are present brain better understanding relative pathogenicity vivo needed. We took advantage fruit fly, Drosophila melanogaster to model examine toxicity each isoform. Our assays reveal 1 be markedly more toxic than 2 all fly tissues. Reduced from due much lower levels result its expedited degradation. Additional indicate aggregation-prone C-terminus critical for enhanced proteasomal According our results, although full-length, pathogenic toxic, likely primary contributor presence at higher levels. Isoform 2, rapid degradation dictated tail, unlikely key player this disease. findings provide new insight into biology ataxia cellular processing underlying protein.