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Review
. 2025 Oct;44(5):483-500.
doi: 10.1007/s10930-025-10287-4. Epub 2025 Aug 30.

Decoding ATXN2 Phosphocode: Structural Insights and Therapeutic Opportunities in Disease

Apoorva Pai Kalasa Anil Kumar  1 , Suhail Subair  1 , Prathik Basthikoppa Shivamurthy  1 , Samseera Ummar  1 , Athira C Rajeev  2 , Rajesh Raju  3
Affiliations
Review

Decoding ATXN2 Phosphocode: Structural Insights and Therapeutic Opportunities in Disease

Apoorva Pai Kalasa Anil Kumar et al. Protein J. 2025 Oct.

Abstract

Ataxin-2 (ATXN2), a key RNA-binding protein, regulates RNA metabolism, stress granule formation, and neuronal homeostasis, with dysregulated phosphorylation contributing to Spinocerebellar Ataxia type 2 (SCA2), amyotrophic lateral sclerosis (ALS), and cancer. This review integrates structural biology, phosphoproteomics, and interactome analyses to map six critical phosphosites (S772, T741, S624, S684, S784, S889) within ATXN2's intrinsically disordered regions. Modulated by kinases GSK3β and CDK13 and phosphatases like INPP5F, these sites orchestrate interactions with RNA-binding partners (e.g., ATXN2L, FXR2, STAU2) and co-regulated proteins (e.g., TP53BP1, NUP153), driving pathogenesis through disrupted autophagy, nucleocytoplasmic transport, and stress granule dynamics. We propose targeted therapies, including GSK3β inhibitors for ALS, antisense oligonucleotides for SCA2, and MTOR modulators for cancer, to restore ATXN2 function. By elucidating phosphocode of ATXN2, this work highlights novel avenues for precision medicine in neurodegenerative and oncogenic diseases.

Keywords: Amyotrophic lateral sclerosis; Ataxin-2; Phosphoproteomics; Spinocerebellar Ataxia type 2.

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Conflict of interest statement

Declarations. Competing interests: The authors declare that they have no competing interests.

References

    1. Carmo-Silva S, Ferreira-Marques M, Nóbrega C, Botelho M, Costa D, Aveleira CA et al (2023) Ataxin-2 in the hypothalamus at the crossroads between metabolism and clock genes. J Mol Endocrinol 70:e210272. https://doi.org/10.1530/JME-21-0272 - DOI - PubMed
    1. Costa RG, Conceição A, Matos CA, Nóbrega C (2024) The polyglutamine protein ATXN2: from its molecular functions to its involvement in disease. Cell Death Dis 15:415 - PubMed - PMC - DOI
    1. Nonhoff U, Ralser M, Welzel F, Piccini I, Balzereit D, Yaspo M-L et al (2007) Ataxin-2 interacts with the DEAD/H-box RNA helicase DDX6 and interferes with P-bodies and stress granules. Mol Biol Cell 18:1385–1396 - PubMed - PMC - DOI
    1. Bakthavachalu B, Huelsmeier J, Sudhakaran IP, Hillebrand J, Singh A, Petrauskas A et al (2018) RNP-granule assembly via Ataxin-2 disordered domains is required for long-term memory and neurodegeneration. Neuron 98:754-766.e4 - PubMed - DOI
    1. Ralser M, Nonhoff U, Albrecht M, Lengauer T, Wanker EE, Lehrach H et al (2005) Ataxin-2 and huntingtin interact with endophilin-A complexes to function in plastin-associated pathways. Hum Mol Genet 14:2893–2909 - PubMed - DOI

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