Atxn1, encoding Ataxin-1, is a dosage-sensitive gene [2,7]. Mutations in it are closely related to spinocerebellar ataxia type 1 (SCA1), an autosomal dominant neurodegenerative disease [1,2,4,5]. The normal function of ATXN1 may be involved in protein-protein interactions, and wild-type polyglutamine regions in ATXN1 are implicated in stabilizing these interactions [3].

In SCA1, the expanded CAG repeat in ATXN1 leads to polyglutamine-expanded ATXN1. These polyQ-expanded ATXN1 form intranuclear inclusion bodies (IIBs) that sequester RNA molecules, potentially affecting ribosome function, protein synthesis, and proteome stability [1]. Reducing the nuclear localization of mutant ATXN1 using CRISPR-Cas9 to alter the nuclear localization sequence (K772T) in mice improves SCA1-like phenotypes such as motor and cognitive deficits, and premature lethality, and also corrects transcriptomic profiles in different brain regions [5]. Additionally, 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 [4]. Intermediate-length polyglutamine expansions in ATXN1 are associated with amyotrophic lateral sclerosis (ALS), especially in C9orf72 expansion carriers, and in functional experiments, ATXN1 affects TDP-43 nucleocytoplasmic ratio and enhances ALS phenotypes in Drosophila [6,8]. miR760 can bind to the 5' untranslated region of ATXN1, regulating its expression, and delivery of AAV-expressing miR760 in the cerebellum reduces ATXN1 levels in vivo and mitigates motor coordination deficits in an SCA1 mouse model [7].

In conclusion, studies on Atxn1, especially through mouse models, have revealed its crucial role in SCA1 and its potential association with ALS. These findings provide insights into the molecular pathogenesis of these neurodegenerative diseases and suggest potential therapeutic strategies, such as gene-editing and miRNA-based therapies.

References:

1. Gkekas, Ioannis, Vagiona, Aimilia-Christina, Pechlivanis, Nikolaos, Andrade-Navarro, Miguel A, Petrakis, Spyros. 2023. Intranuclear inclusions of polyQ-expanded ATXN1 sequester RNA molecules. In Frontiers in molecular neuroscience, 16, 1280546. doi:10.3389/fnmol.2023.1280546. https://pubmed.ncbi.nlm.nih.gov/38125008/

2. Xie, Mingyi, Swanson, Maurice S. . UTteR control through miRs: fine-tuning ATXN1 levels to prevent ataxia. In Genes & development, 34, 1107-1109. doi:10.1101/gad.343020.120. https://pubmed.ncbi.nlm.nih.gov/32873576/

3. Rocha, Sara, Vieira, Jorge, Vázquez, Noé, Sousa, André D, Vieira, Cristina P. 2019. ATXN1 N-terminal region explains the binding differences of wild-type and expanded forms. In BMC medical genomics, 12, 145. doi:10.1186/s12920-019-0594-4. https://pubmed.ncbi.nlm.nih.gov/31655597/

4. Fagan, Kelly J, Chillon, Guillem, Carrell, Ellie M, Waxman, Elisa A, Davidson, Beverly L. 2024. Cas9 editing of ATXN1 in a spinocerebellar ataxia type 1 mice and human iPSC-derived neurons. In Molecular therapy. Nucleic acids, 35, 102317. doi:10.1016/j.omtn.2024.102317. https://pubmed.ncbi.nlm.nih.gov/39314800/

5. Handler, Hillary P, Duvick, Lisa, Mitchell, Jason S, Zoghbi, Huda Y, Orr, Harry T. 2022. Decreasing mutant ATXN1 nuclear localization improves a spectrum of SCA1-like phenotypes and brain region transcriptomic profiles. In Neuron, 111, 493-507.e6. doi:10.1016/j.neuron.2022.11.017. https://pubmed.ncbi.nlm.nih.gov/36577403/

6. Lattante, Serena, Pomponi, Maria Grazia, Conte, Amelia, Zollino, Marcella, Sabatelli, Mario. 2017. ATXN1 intermediate-length polyglutamine expansions are associated with amyotrophic lateral sclerosis. In Neurobiology of aging, 64, 157.e1-157.e5. doi:10.1016/j.neurobiolaging.2017.11.011. https://pubmed.ncbi.nlm.nih.gov/29274668/

7. Nitschke, Larissa, Tewari, Ambika, Coffin, Stephanie L, Liu, Zhandong, Zoghbi, Huda Y. 2020. miR760 regulates ATXN1 levels via interaction with its 5' untranslated region. In Genes & development, 34, 1147-1160. doi:10.1101/gad.339317.120. https://pubmed.ncbi.nlm.nih.gov/32763910/

8. Tazelaar, Gijs H P, Boeynaems, Steven, De Decker, Mathias, Veldink, Jan H, van Es, Michael A. 2020. ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization. In Brain communications, 2, fcaa064. doi:10.1093/braincomms/fcaa064. https://pubmed.ncbi.nlm.nih.gov/32954321/