Atxn2, also known as ataxin-2, is a gene with a CAG repeat sequence encoding a polyglutamine (polyQ) tract within the ataxin-2 protein. This multifaceted protein is a key player in RNA metabolism, stress granules dynamics, endocytosis, calcium signaling, and the regulation of the circadian rhythm [1]. It is also involved in pathways related to various diseases, making it an important target for genetic model-based studies.

In terms of disease associations, an overexpansion of the CAG repeat in the ATXN2 gene is mainly linked to spinocerebellar ataxia type 2 (SCA2), and intermediate expansions are implicated in amyotrophic lateral sclerosis (ALS) and parkinsonism [1]. Intermediate CAG (polyQ) expansions in ATXN2, specifically ≥31 repeats, are recognized as a risk factor for ALS, with an even greater risk for ALS with frontotemporal dementia [3]. Gene therapy clinical trials are underway for ALS patients with ATXN2 trinucleotide expansions [4]. In esophageal squamous cell carcinoma (ESCC), ATXN2, as a functional protein in m6A methylation, augments the translation of TNFRSF1A, activating the NF-κB and MAPK pathways and promoting ESCC development [2]. In gastric cancer, ATXN2, by activating the PI3K/AKT pathway, promotes chemoresistance and facilitates immune escape [5].

In conclusion, Atxn2 is crucial in multiple biological processes and is significantly associated with various neurodegenerative and cancer diseases. Studies, including those using potential KO/CKO mouse models (although not detailed in the provided abstracts), could further clarify its role in these diseases, potentially leading to new therapeutic strategies for SCA2, ALS, and certain cancers [1,2,3,4,5].

References:

1. Costa, Rafael G, Conceição, André, Matos, Carlos A, Nóbrega, Clévio. 2024. The polyglutamine protein ATXN2: from its molecular functions to its involvement in disease. In Cell death & disease, 15, 415. doi:10.1038/s41419-024-06812-5. https://pubmed.ncbi.nlm.nih.gov/38877004/

2. Li, Rui, Zeng, Lingxing, Zhao, Hongzhe, Zheng, Jian, Huang, Xudong. 2022. ATXN2-mediated translation of TNFR1 promotes esophageal squamous cell carcinoma via m6A-dependent manner. In Molecular therapy : the journal of the American Society of Gene Therapy, 30, 1089-1103. doi:10.1016/j.ymthe.2022.01.006. https://pubmed.ncbi.nlm.nih.gov/34995801/

3. Glass, Jonathan D, Dewan, Ramita, Ding, Jinhui, Chia, Ruth, Landers, John E. . ATXN2 intermediate expansions in amyotrophic lateral sclerosis. In Brain : a journal of neurology, 145, 2671-2676. doi:10.1093/brain/awac167. https://pubmed.ncbi.nlm.nih.gov/35521889/

4. Amado, Defne A, Davidson, Beverly L. 2021. Gene therapy for ALS: A review. In Molecular therapy : the journal of the American Society of Gene Therapy, 29, 3345-3358. doi:10.1016/j.ymthe.2021.04.008. https://pubmed.ncbi.nlm.nih.gov/33839324/

5. Wang, Qi, Cao, Tianyu, Zhang, Xiaohui, Zhou, Yun, Han, Shuang. 2022. ATXN2-Mediated PI3K/AKT Activation Confers Gastric Cancer Chemoresistance and Attenuates CD8+ T Cell Cytotoxicity. In Journal of immunology research, 2022, 6863240. doi:10.1155/2022/6863240. https://pubmed.ncbi.nlm.nih.gov/36213324/