Bioinformatics Analysis of Ataxin-3’s Transcriptional Regulation in Nervous System Inflammation, Metabolism, and Angiogenesis
The Third Xiangya Hospital, Central South University, Changsha 410013, China
| Abstract: | Utilizing principles of bioinformatics, this study endeavors to elucidate the role of Ataxin-3 in gene expression regulation and propose novel research avenues to unravel the pathophysiological mechanisms of Spinocerebellar Ataxia Type 3 (SCA3), attributed to the functional impairment and deficiency of Ataxin-3. This study accessed the Gene Expression Omnibus (GEO) database to obtain microarray data (GSE117028) from both normal and Atxn3 knockout Mouse embryonic fibroblasts (MEFs), aiming to identify differentially expressed genes (DEGs). Tissue expression specificity was analyzed using the BioGPS database. The DAVID 2021 analysis platform is utilized for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. A protein-protein interaction (PPI) network for DEGs was constructed with the STRING database, and PPI data visualization was achieved through the Cytoscape software, with the hub-DEGs identified using the CytoHubba plugin. Enrichment analysis of key differentially expressed proteins and transcriptional regulatory network construction were performed using DAVID 2021 and Cistrome DB databases. Our analysis identified 164 DEGs, which showed pronounced expression specificity in the nervous and immune systems. GO analysis indicated that these DEGs are extensively involved in processes such as multicellular organism development, cell adhesion, and angiogenesis. KEGG analysis highlighted the involvement of DEGs in metabolic processes, immune pathways mediated by cytokines and chemokines, and the IL-17 signaling pathway. PPI network analysis identified six hub proteins: Cxcl1, Cxcl5, Saa3, Eng, Thy1, and Lpl, playing significant roles in the immune-inflammatory pathway. Additionally, transcription factors (TFs) CEBPB, STAT5A, NR3C1, SPI1, and EP300 were found to exert regulatory functions within these pathways. The impairment of Ataxin-3's regulatory function across various signaling pathways is hypothesized to contribute to the pathogenesis of SCA3. These findings suggest that restoring Ataxin-3 function could represent a potential therapeutic strategy for SCA3. |
| Keywords: | Ataxin-3; Inflammation; Metabolism; Angiogenesis; Transcriptional Regulation; Bioinformatics |
| DOI: | 10.57237/j.cmf.2025.02.001 |
View:
Downloads:
Received: 5 June 2025
Accepted: 24 July 2025
Published Online: 9 September 2025
References
| [1] | Matos CA, de Almeida LP, Nóbrega C. Machado-Joseph disease/spinocerebellar ataxia type 3: lessons from disease pathogenesis and clues into therapy. J Neurochem. 2019; 148(1): 8-28. |
| [2] | Simões AT, Gonçalves N, Koeppen A, et al. Calpastatin-mediated inhibition of calpains in the mouse brain prevents mutant ataxin 3 proteolysis, nuclear localization and aggregation, relieving Machado-Joseph disease. Brain. 2012; 135(Pt 8): 2428-2439. |
| [3] | Wu Y, Peng Y, Wang Y. An insight into advances in the pathogenesis and therapeutic strategies of spinocerebellar ataxia type 3. Rev Neurosci. 2015; 26(1): 95-104. |
| [4] | Raposo M, Bettencourt C, Ramos A, et al. Promoter Variation and Expression Levels of Inflammatory Genes IL1A, IL1B, IL6 and TNF in Blood of Spinocerebellar Ataxia Type 3(SCA3) Patients. Neuromolecular Med. 2017; 19(1): 41-45. |
| [5] | Carvalho AL, Silva A, Macedo-Ribeiro S. Polyglutamine-Independent Features in Ataxin-3 Aggregation and Pathogenesis of Machado-Joseph Disease. Adv Exp Med Biol. 2018; 1049: 275 -288. |
| [6] | Li X, Liu H, Fischhaber PL, Tang TS. Toward therapeutic targets for SCA3: Insight into the role of Machado-Joseph disease protein ataxin-3 in misfolded proteins clearance. Prog Neurobiol. 2015; 132: 34-58. |
| [7] | McLoughlin HS, Moore LR, Paulson HL. Pathogenesis of SCA3 and implications for other polyglutamine diseases. Neurobiol Dis. 2020; 134: 104635. |
| [8] | Rodrigues AJ, Neves-Carvalho A, Teixeira-Castro A, et al. Absence of ataxin-3 leads to enhanced stress response in C. elegans. PLoS One. 2011; 6(4): e18512. Published 2011 Apr 19. |
| [9] | do Carmo Costa M, Bajanca F, Rodrigues AJ, et al. Ataxin-3 plays a role in mouse myogenic differentiation through regulation of integrin subunit levels. PLoS One. 2010; 5(7): e11728. |
| [10] | Rodrigues AJ, Coppola G, Santos C, et al. Functional genomics and biochemical characterization of the C. elegans orthologue of the Machado-Joseph disease protein ataxin-3. FASEB J. 2007; 21(4): 1126-1136. |
| [11] | Zeng L, Zhang D, McLoughlin HS, Zalon AJ, Aravind L, Paulson HL. Loss of the Spinocerebellar Ataxia type 3 disease protein ATXN3 alters transcription of multiple signal transduction pathways. PLoS One. 2018 Sep 19; 13(9): e0204438. |
| [12] | Paulino R, Nóbrega C. Autophagy in Spinocerebellar Ataxia Type 3: From Pathogenesis to Therapeutics. Int J Mol Sci. 2023 Apr 17; 24(8): 7405. |
| [13] | Warrick JM, Morabito LM, Bilen J, et al. Ataxin-3 suppresses polyglutamine neurodegeneration in Drosophila by a ubiquitin-associated mechanism. Mol Cell. 2005; 18(1): 37-48. |
| [14] | Schmitt I, Linden M, Khazneh H, et al. Inactivation of the mouse Atxn3(ataxin-3) gene increases protein ubiquitination. Biochem Biophys Res Commun. 2007; 362(3): 734-739. |
| [15] | Switonski PM, Fiszer A, Kazmierska K, Kurpisz M, Krzyzosiak WJ, Figiel M. Mouse ataxin-3 functional knock-out model. Neuromolecular Med. 2011; 13(1): 54-65. |
| [16] | Rodrigues AJ, do Carmo Costa M, Silva TL, et al. Absence of ataxin-3 leads to cytoskeletal disorganization and increased cell death. Biochim Biophys Acta. 2010; 1803(10): 1154-1163. |
| [17] | Evert BO, Vogt IR, Vieira-Saecker AM, et al. Gene expression profiling in ataxin-3 expressing cell lines reveals distinct effects of normal and mutant ataxin-3. J Neuropathol Exp Neurol. 2003; 62(10): 1006-1018. |
| [18] | Yang J, Zhan XZ, Malola J, et al. The multiple roles of Thy-1 in cell differentiation and regeneration. Differentiation. 2020; 113: 38-48. |
| [19] | Sowa AS, Popova TG, Harmuth T, et al. Neurodegenerative phosphoprotein signaling landscape in models of SCA3. Mol Brain. 2021; 14(1): 57. |
| [20] | Korbecki J, Gąssowska-Dobrowolska M, Wójcik J, et al. The Importance of CXCL1 in Physiology and Noncancerous Diseases of Bone, Bone Marrow, Muscle and the Nervous System. Int J Mol Sci. 2022; 23(8): 4205. |
| [21] | Sowa AS, Haas E, Hübener-Schmid J, Lorentz A. Ataxin-3, The Spinocerebellar Ataxia Type 3 Neurodegenerative Disorder Protein, Affects Mast Cell Functions. Front Immunol. 2022; 13: 870966. |
| [22] | Lindborg JA, Niemi JP, Howarth MA, et al. Molecular and cellular identification of the immune response in peripheral ganglia following nerve injury. J Neuroinflammation. 2018; 15(1): 192. |
| [23] | Czapski GA, Zhao Y, Lukiw WJ, Strosznajder JB. Acute Systemic Inflammatory Response Alters Transcription Profile of Genes Related to Immune Response and Ca2+ Homeostasis in Hippocampus; Relevance to Neurodegenerative Disorders. Int J Mol Sci. 2020; 21(21): 7838. |
| [24] | Lin YT, Lin YS, Cheng WL, et al. Transcriptomic and Metabolic Network Analysis of Metabolic Reprogramming and IGF-1 Modulation in SCA3 Transgenic Mice. Int J Mol Sci. 2021; 22(15): 7974. |
| [25] | Chapman TP, Corridoni D, Shiraishi S, Pandey S, Aulicino A, Wigfield S, do Carmo Costa M, Thézénas ML, Paulson H, Fischer R, Kessler BM, Simmons A. Ataxin-3 Links NOD2 and TLR2 Mediated Innate Immune Sensing and Metabolism in Myeloid Cells. Front Immunol. 2019 Jul 19; 10: 1495. |
| [26] | Yu T, Taussig MD, DiPatrizio NV, Astarita G, Piomelli D, Bergman BC, Dell'Acqua ML, Eckel RH, Wang H. Deficiency of Lipoprotein Lipase in Neurons Decreases AMPA Receptor Phosphorylation and Leads to Neurobehavioral Abnormalities in Mice. PLoS One. 2015 Aug 11; 10(8): e0135113. |
| [27] | Duarte Lobo D, Nobre RJ, Oliveira Miranda C, et al. The blood-brain barrier is disrupted in Machado-Joseph disease/spinocerebellar ataxia type 3: evidence from transgenic mice and human post-mortem samples. Acta Neuropathol Commun. 2020; 8(1): 152. |
| [28] | Iłzecka J. Decreased serum endoglin level in patients with amyotrophic lateral sclerosis: a preliminary report. Scand J Clin Lab Invest. 2008; 68(4): 348-351. |
| [29] | Evert BO, Araujo J, Vieira-Saecker AM, de Vos RA, Harendza S, Klockgether T, Wüllner U. Ataxin-3 represses transcription via chromatin binding, interaction with histone deacetylase 3, and histone deacetylation. J Neurosci. 2006 Nov 1; 26(44): 11474-86. |
| [30] | Rubio K, Molina-Herrera A, Pérez-González A, Hernández-Galdámez HV, Piña-Vázquez C, Araujo-Ramos T, Singh I. EP300 as a Molecular Integrator of Fibrotic Transcriptional Programs. Int J Mol Sci. 2023 Aug 1; 24(15): 12302. |
| [31] | Li F, Macfarlan T, Pittman RN, Chakravarti D. Ataxin-3 is a histone-binding protein with two independent transcriptional corepressor activities. J Biol Chem. 2002 Nov 22; 277(47): 45004-12. |
Join the Editorial Board
We invite active, qualified and high profile scientists and researchers to join as Editorial Board Members.
Join UsBecome a Reviewer
Scholars with a strong interest in reviewing are invited to join the reviewer panel to ensure the quality of the research to be published.
Join Us