Atxn1, encoding Ataxin-1, is a dosage-sensitive gene closely associated with spinocerebellar ataxia type 1 (SCA1) [1,2,3,5,6]. Its precise expression levels are crucial, as even subtle variations in wild-type Atxn1 levels can lead to ataxia [1]. The protein may be involved in multiple cellular processes, though the exact pathways are still being elucidated. Genetic models, such as mouse models, are valuable for studying Atxn1's function.

In SCA1, a trinucleotide (CAG) repeat expansion in the Atxn1 gene causes the disease. Mutant ATXN1 with polyglutamine expansion forms intranuclear inclusion bodies that sequester RNA molecules, potentially affecting ribosome function and proteome stability [2]. Additionally, post-transcriptional events, like the interaction between the 5' untranslated region of Atxn1 and miR760, fine-tune its expression, and delivering AAV-expressing miR760 can reduce Atxn1 levels and mitigate motor deficits in SCA1 mouse models [6]. Intermediate-length polyglutamine expansions in Atxn1 are associated with amyotrophic lateral sclerosis (ALS), especially in C9orf72 expansion carriers [4,7]. Functional experiments show that Atxn1 can reduce the nucleocytoplasmic ratio of TDP-43 and enhance ALS phenotypes in Drosophila [7]. Cas9 editing of Atxn1 in SCA1 mouse models and human iPSC-derived neurons shows potential as a treatment modality, as a 20% reduction of ATXN1 improved behavior deficits without increasing inflammatory markers [3].

In conclusion, Atxn1's tight regulation is essential for normal function, and its dysregulation is implicated in neurodegenerative diseases like SCA1 and ALS. Studies using mouse models and other experimental systems have provided insights into its role in these diseases, highlighting its potential as a therapeutic target for SCA1 and possibly ALS.