Ataxin-2 (ATXN2) (ATXN2)

Ataxin-2 is a widely expressed cytoplasmic RNA-binding protein involved in various aspects of RNA metabolism, including translation regulation, mRNA stability, and the formation of stress granules (UniProt Q99700). It is encoded by the ATXN2 gene, which contains a polymorphic CAG trinucleotide repeat sequence. Pathological expansion of this CAG repeat (typically >34 repeats) leads to the production of a polyglutamine-expanded protein, causing Spinocerebellar ataxia type 2 (SCA2), a progressive neurodegenerative disorder. Furthermore, intermediate-length CAG expansions (27-33 repeats) in ATXN2 are a significant genetic risk factor for Amyotrophic lateral sclerosis (ALS) (PubMed: 20739679). Ataxin-2 has been shown to interact with and stabilize TDP-43, a protein that forms toxic aggregates in the majority of ALS cases. Therapeutic strategies currently focus on reducing Ataxin-2 expression using antisense oligonucleotides (ASOs) to mitigate its toxic gain-of-function and its role in stabilizing TDP-43 aggregates. Clinical candidates like BIIB105 are currently being evaluated for their ability to lower Ataxin-2 levels and slow disease progression in patients with ALS (ClinicalTrials.gov: NCT04494256).

Other names

SCA2ASL13TNRC13Trinucleotide repeat-containing gene 13 protein

Antisense oligonucleotides (ASOs) are designed to bind to ATXN2 mRNA and trigger its degradation via RNase H, thereby reducing the levels of the Ataxin-2 protein to mitigate toxic gain-of-function and protein aggregation.