Ataxin-3 pre-messenger RNA exon 10 (ATXN3 exon 10)

Ataxin-3 (ATXN3) is a deubiquitinating enzyme involved in protein quality control and the ubiquitin-proteasome system [1]. The ATXN3 gene contains a polymorphic CAG repeat sequence in exon 10, which encodes a polyglutamine (polyQ) tract in the resulting protein [1, 2]. Expansion of this CAG repeat beyond a certain threshold causes Spinocerebellar Ataxia Type 3 (SCA3), also known as Machado-Joseph disease, a progressive neurodegenerative disorder [2]. The expanded polyQ tract leads to protein misfolding, aggregation, and gain-of-toxic-function in neurons [2, 3]. Targeting the exon 10 region of the ATXN3 pre-mRNA is a primary therapeutic strategy to reduce the production of the toxic mutant protein [2]. Antisense oligonucleotides (ASOs) can be designed to bind this region to induce exon skipping, which removes the CAG expansion while maintaining an open reading frame [2, 3]. This approach aims to produce a truncated but potentially functional ataxin-3 protein that lacks the toxic polyglutamine expansion [3]. Other RNA-targeted therapies, such as RNA interference or RNase H-active ASOs, may also target this region or adjacent sequences to lower overall ATXN3 expression [4]. Clinical development of these therapies focuses on slowing disease progression and improving motor function in SCA3 patients [4]. Sources: [1] UniProt (P54252) [2] Evers et al. (2013) Molecular Therapy [3] Toonen et al. (2017) Molecular Therapy Nucleic Acids [4] McLoughlin et al. (2018) JAMA Neurology

Other names

MJD1 pre-mRNA exon 10Machado-Joseph disease protein 1 pre-mRNA exon 10ATXN3 CAG repeat regionAtaxin-3 exon 10

Exon skipping and RNA degradation