{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T03:35:48Z","timestamp":1778297748866,"version":"3.51.4"},"reference-count":64,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,12,15]],"date-time":"2023-12-15T00:00:00Z","timestamp":1702598400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:p>Ataxia with oculomotor apraxia type 1 (AOA1) is a progressive neurodegenerative disorder characterized by a gradual loss of coordination of hand movements, speech, and eye movements. AOA1 is caused by an inactivation mutation in the <jats:italic>APTX<\/jats:italic> gene. APTX resolves abortive DNA ligation intermediates. APTX deficiency may lead to the accumulation of 5\u2019-AMP termini, especially in the mitochondrial genome. The consequences of APTX deficiency includes impaired mitochondrial function, increased DNA single-strand breaks, elevated reactive oxygen species production, and altered mitochondrial morphology. All of these processes can cause misplacement of nuclear and mitochondrial DNA, which can activate innate immune sensors to elicit an inflammatory response. This study explores the impact of APTX knockout in microglial cells, the immune cells of the brain. RNA-seq analysis revealed significant differences in the transcriptomes of wild-type and APTX knockout cells, especially in response to viral infections and innate immune pathways. Specifically, genes and proteins involved in the cGAS-STING and RIG-I\/MAVS pathways were downregulated in APTX knockout cells, which suggests an impaired immune response to cytosolic DNA and RNA. The clinical relevance of these findings was supported by analyzing publicly available RNA-seq data from AOA1 patient cell lines. Comparisons between APTX-deficient patient cells and healthy control cells also revealed altered immune responses and dysregulated DNA- and RNA-sensing pathways in the patient cells. Overall, this study highlights the critical role of APTX in regulating innate immunity, particularly in DNA- and RNA-sensing pathways. Our findings contribute to a better understanding of the underlying molecular mechanisms of AOA1 pathology and highlights potential therapeutic targets for this disease.<\/jats:p>","DOI":"10.3389\/fnagi.2023.1290681","type":"journal-article","created":{"date-parts":[[2023,12,15]],"date-time":"2023-12-15T11:04:10Z","timestamp":1702638250000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["The DNA repair enzyme, aprataxin, plays a role in innate immune signaling"],"prefix":"10.3389","volume":"15","author":[{"given":"Helena B.","family":"Madsen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Louise I.","family":"Pease","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebekah-Louise","family":"Scanlan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mansour","family":"Akbari","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lene J.","family":"Rasmussen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daryl P.","family":"Shanley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vilhelm A.","family":"Bohr","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,12,15]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1038\/nature05164","article-title":"The neurodegenerative disease protein aprataxin resolves abortive DNA ligation intermediates","volume":"443","author":"Ahel","year":"2006","journal-title":"Nature"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1007\/S10048-009-0206-0\/METRICS","article-title":"Characterization of two novel SETX mutations in AOA2 patients reveals aspects of the pathophysiological role of senataxin","volume":"11","author":"Airoldi","year":"2010","journal-title":"Neuroge."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"3544","DOI":"10.3390\/cells10123544","article-title":"Cytosolic self-DNA\u2014A potential source of chronic inflammation in aging","volume":"10","author":"Akbari","year":"2021","journal-title":"Cells"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"12876","DOI":"10.1038\/srep12876","article-title":"Slow mitochondrial repair of 5\u2032-AMP renders mtDNA susceptible to damage in APTX deficient cells","volume":"5","author":"Akbari","year":"2015","journal-title":"Sci. Rep."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"720490","DOI":"10.3389\/FCELL.2021.720490\/BIBTEX","article-title":"Metabolism and innate immunity meet at the mitochondria","volume":"9","author":"Bahat","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"9293","DOI":"10.1021\/ja110190t","article-title":"Calcium binding and transport by coenzyme Q","volume":"133","author":"Bogeski","year":"2011","journal-title":"J. Am. Chem. Soc."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"474","DOI":"10.1016\/j.ajhg.2015.01.005","article-title":"Mutations in PNKP cause recessive Ataxia with oculomotor apraxia type 4","volume":"96","author":"Bras","year":"2015","journal-title":"Am. J. Hum. Genet."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1016\/j.molcel.2014.03.040","article-title":"The cGAS-cGAMP-STING pathway of cytosolic DNA sensing and signaling","volume":"54","author":"Cai","year":"2014","journal-title":"Mol. Cell"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1038\/EMBOR.2009.258","article-title":"Mitochondrial dynamics regulate the RIG-I-like receptor antiviral pathway","volume":"11","author":"Castanier","year":"2010","journal-title":"EMBO Rep."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"S1355838298980724","DOI":"10.1017\/S1355838298980724","article-title":"More than one way to splice an RNA: branching without a bulge and splicing without branching in group II introns","volume":"4","author":"Chu","year":"1998","journal-title":"RNA"},{"key":"ref12","author":"Coutinho","year":"2023"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"832","DOI":"10.3389\/fimmu.2017.00832","article-title":"Human leukocyte antigen (HLA) and immune regulation: how do classical and non-classical HLA alleles modulate immune response to human immunodeficiency virus and hepatitis C virus infections?","volume":"8","author":"Crux","year":"2017","journal-title":"Front. Immunol."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"804","DOI":"10.1006\/BBRC.1997.7059","article-title":"Increased transcript level of RBM3, a member of the Glycine-rich RNA-binding protein family, in human cells in response to cold stress","volume":"236","author":"Danno","year":"1997","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"2829","DOI":"10.4049\/JIMMUNOL.1400840","article-title":"Stimulation of the RIG-I\/MAVS pathway by Polyinosinic:Polycytidylic acid upregulates IFN-\u03b2 in airway epithelial cells with minimal Costimulation of IL-8","volume":"195","author":"Dauletbaev","year":"2015","journal-title":"J. Immunol."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1016\/J.CELL.2010.04.018","article-title":"Peroxisomes are signaling platforms for antiviral innate immunity","volume":"141","author":"Dixit","year":"2010","journal-title":"Cells"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"1865","DOI":"10.1073\/pnas.0409764102","article-title":"Cold stress-induced protein Rbm3 binds 60S ribosomal subunits, alters microRNA levels, and enhances global protein synthesis","volume":"102","author":"Dresios","year":"2005","journal-title":"Proc. Natl. Acad. Sci."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1186\/1479-5876-8-78","article-title":"Expression of the RNA-binding protein RBM3 is associated with a favourable prognosis and cisplatin sensitivity in epithelial ovarian cancer","volume":"8","author":"Ehl\u00e9n","year":"2010","journal-title":"J. Transl. Med."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"882","DOI":"10.1016\/J.CELL.2014.03.026","article-title":"Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)\/SIRT1 reduction","volume":"157","author":"Fang","year":"2014","journal-title":"Cells"},{"key":"ref20","author":"Fu","year":"2023"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"1440","DOI":"10.1126\/science.aan6160","article-title":"Structural basis of membrane disruption and cellular toxicity by a-synuclein oligomers","volume":"358","author":"Fusco","year":"2017","journal-title":"Science"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1186\/s13073-021-00870-6","article-title":"Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders","volume":"13","author":"Gillentine","year":"2021","journal-title":"Genome Med."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1016\/j.jtbi.2018.11.001","article-title":"Mathematical modeling of the cGAS pathway reveals robustness of DNA sensing to TREX1 feedback","volume":"462","author":"Gregg","year":"2019","journal-title":"J. Theor. Biol."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"e2011226118","DOI":"10.1073\/PNAS.2011226118\/-\/DCSUPPLEMENTAL","article-title":"NAD+ supplementation reduces neuroinflammation and cell senescence in a transgenic mouse model of Alzheimer\u2019s disease via cGAS-STING","volume":"118","author":"Hou","year":"2021","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref1002","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1007\/S00115-012-3637-Z","article-title":"The genetics of spinocerebellar ataxias","volume":"84","author":"Jacobi","year":"2013","journal-title":"Der Nervenarzt."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"108776","DOI":"10.1016\/j.clim.2021.108776","article-title":"Immunological abnormalities in patients with early-onset ataxia with ocular motor apraxia and hypoalbuminemia","volume":"229","author":"Kato","year":"2021","journal-title":"Clin. Immunol."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"13939","DOI":"10.1074\/jbc.M507946200","article-title":"Aprataxin forms a discrete branch in the HIT (histidine triad) superfamily of proteins with both DNA\/RNA binding and nucleotide hydrolase activities","volume":"281","author":"Kijas","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"S391","DOI":"10.1016\/S1353-8020(08)70036-1","article-title":"Ataxias","volume":"13","author":"Klockgether","year":"2007","journal-title":"Parkinsonism Relat. Disord."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"2859","DOI":"10.3389\/fonc.2021.682859","article-title":"HNRNPH1 is a novel regulator of cellular proliferation and disease progression in chronic myeloid leukemia","volume":"11","author":"Liu","year":"2021","journal-title":"Front. Oncol."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"17023","DOI":"10.1038\/sigtrans.2017.23","article-title":"NF-\u03baB signaling in inflammation","volume":"2","author":"Liu","year":"2017","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/S13059-014-0550-8\/FIGURES\/9","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"1830","DOI":"10.1093\/BIOINFORMATICS\/BTT285","article-title":"Pathview: an R\/Bioconductor package for pathway-based data integration and visualization","volume":"29","author":"Luo","year":"2013","journal-title":"Bioinformatics"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.bbrc.2011.06.038","article-title":"Generation of mice deficient in RNA-binding motif protein 3 (RBM3) and characterization of its role in innate immune responses and cell growth","volume":"411","author":"Matsuda","year":"2011","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1016\/J.BBI.2021.04.016","article-title":"Double stranded RNA drives anti-viral innate immune responses, sickness behavior and cognitive dysfunction dependent on dsRNA length, IFNAR1 expression and age","volume":"95","author":"McGarry","year":"2021","journal-title":"Brain Behav. Immun."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1038\/ng1001-189","article-title":"The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT\/Zn-finger protein aprataxin","volume":"29","author":"Moreira","year":"2001","journal-title":"Nat. Genet."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"1731","DOI":"10.1261\/rna.072454.119","article-title":"HNRNPH1-dependent splicing of a fusion oncogene reveals a targetable RNA G-quadruplex interaction","volume":"25","author":"Neckles","year":"2019","journal-title":"RNA"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/0960-8966(95)00020-8","article-title":"The influence of coenzyme Q10 on total serum calcium concentration in two patients with kearns-Sayre syndrome and hypoparathyroidism","volume":"6","author":"Papadimitriou","year":"1996","journal-title":"Neuromuscul. Disord."},{"key":"ref37","author":"Pasmanter","year":"2023"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1038\/nmeth.4197","article-title":"Salmon provides fast and bias-aware quantification of transcript expression","volume":"14","author":"Patro","year":"2017","journal-title":"Nat. Methods"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"e49","DOI":"10.1212\/NXG.0000000000000049","article-title":"Expanding the ataxia with oculomotor apraxia type 4 phenotype","volume":"2","author":"Paucar","year":"2016","journal-title":"Neurol. Genet."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"708","DOI":"10.7916\/tohm.v0.708","article-title":"Progressive Ataxia with elevated alpha-fetoprotein: diagnostic issues and review of the literature","volume":"9","author":"Paucar","year":"2019","journal-title":"Tremor Other Hyperkinet Mov (N Y)"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1212\/01.WNL.0000150588.75281.58","article-title":"Coenzyme Q deficiency and cerebellar ataxia associated with an aprataxin mutation","volume":"64","author":"Quinzii","year":"2005","journal-title":"Neurology"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"9469","DOI":"10.1074\/jbc.M611489200","article-title":"Actions of Aprataxin in multiple DNA repair pathways","volume":"282","author":"Rass","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"e96553","DOI":"10.15252\/EMBJ.201796553","article-title":"Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency","volume":"37","author":"Rodr\u00edguez-Nuevo","year":"2018","journal-title":"EMBO J."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"058","DOI":"10.1055\/S-0039-1684008","article-title":"Ataxia with oculomotor apraxia type 4 with PNKP common \u201cPortuguese\u201d and novel mutations in two Belarusian families","volume":"8","author":"Rudenskaya","year":"2019","journal-title":"J Pediatr Genet"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1002\/ana.10808","article-title":"Aprataxin, the causative protein for EAOH is a nuclear protein with a potential role as a DNA repair protein","volume":"55","author":"Sano","year":"2004","journal-title":"Ann. Neurol."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"1367","DOI":"10.1111\/J.1471-4159.2007.04521.X","article-title":"Two isoforms of the cold-inducible mRNA-binding protein RBM3 localize to dendrites and promote translation","volume":"101","author":"Smart","year":"2007","journal-title":"J. Neurochem."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"114934","DOI":"10.1016\/J.BCP.2022.114934","article-title":"Second messenger 2\u20323\u2032-cyclic GMP\u2013AMP (2\u20323\u2032-cGAMP): synthesis, transmission, and degradation","volume":"198","author":"Su","year":"2022","journal-title":"Biochem. Pharmacol."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"R730","DOI":"10.1016\/j.cub.2022.05.027","article-title":"cGAS\u2013STING signaling","volume":"32","author":"Sun","year":"2022","journal-title":"Curr. Biol."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"D605","DOI":"10.1093\/nar\/gkaa1074","article-title":"The STRING database in 2021: customizable protein\u2013protein networks, and functional characterization of user-uploaded gene\/measurement sets","volume":"49","author":"Szklarczyk","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1007\/978-1-4419-6448-9_3","article-title":"Early-onset Ataxia with ocular motor apraxia and hypoalbuminemia\/Ataxia with oculomotor apraxia","author":"Tada","year":"2010","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1002\/HUMU.21650","article-title":"A missense mutation in PIK3R5 gene in a family with ataxia and oculomotor apraxia","volume":"33","author":"Tassan","year":"2012","journal-title":"Hum. Mutat."},{"key":"ref51","doi-asserted-by":"publisher","DOI":"10.18129\/B9.bioc.KEGGREST","article-title":"Client-side REST access to the Kyoto encyclopedia of genes and genomes (KEGG)","author":"Tenenbaum","year":"2022","journal-title":"KEGGREST"},{"key":"ref52","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1038\/nature12824","article-title":"Aprataxin resolves adenylated RNA\u2013DNA junctions to maintain genome integrity","volume":"506","author":"Tumbale","year":"2014","journal-title":"Nature"},{"key":"ref53","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/J.CLIM.2017.01.009","article-title":"Ataxia-telangiectasia: immunodeficiency and survival","volume":"178","author":"van Os","year":"2017","journal-title":"Clin. Immunol."},{"key":"ref54","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1038\/S41586-023-06621-4","article-title":"Apoptotic stress causes mtDNA release during senescence and drives the SASP","volume":"622","author":"Victorelli","year":"2023","journal-title":"Nature"},{"key":"ref1003","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1136\/jnnp.43.2.111","article-title":"Lipids and lipoproteins in Friedreich\u2019s ataxia","volume":"43","author":"Walker","year":"1980","journal-title":"J. Neuro. Neurosur. Psych."},{"key":"ref55","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1038\/NATURE14156","article-title":"Mitochondrial DNA stress primes the antiviral innate immune response","volume":"520","author":"West","year":"2015","journal-title":"Nature"},{"key":"ref56","doi-asserted-by":"publisher","first-page":"100141","DOI":"10.1016\/J.XINN.2021.100141","article-title":"clusterProfiler 4.0: a universal enrichment tool for interpreting omics data","volume":"2","author":"Wu","year":"2021","journal-title":"The Innovation"},{"key":"ref57","doi-asserted-by":"publisher","first-page":"17156","DOI":"10.1038\/s41467-020-17156-x","article-title":"Interferon-independent STING signaling promotes resistance to HSV-1 in vivo","volume":"11","author":"Yamashiro","year":"2020","journal-title":"Nat. Commun."},{"key":"ref58","doi-asserted-by":"publisher","first-page":"872134","DOI":"10.3389\/FNAGI.2022.872134\/BIBTEX","article-title":"The emerging role of central and peripheral immune systems in neurodegenerative diseases","volume":"14","author":"Zang","year":"2022","journal-title":"Front. Aging Neurosci."},{"key":"ref59","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1016\/J.IT.2016.12.004","article-title":"Cross-talk between the cytoplasmic RIG-I and STING sensing pathways","volume":"38","author":"Zevini","year":"2017","journal-title":"Trends Immunol."},{"key":"ref60","doi-asserted-by":"publisher","first-page":"4086","DOI":"10.1093\/nar\/gkz083","article-title":"Diminished OPA1 expression and impaired mitochondrial morphology and homeostasis in Aprataxin-deficient cells","volume":"47","author":"Zheng","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref61","doi-asserted-by":"publisher","first-page":"67819","DOI":"10.3389\/FIMMU.2013.00333","article-title":"Functions of NOD-like receptors in human diseases","volume":"4","author":"Zhong","year":"2013","journal-title":"Front. Immunol."},{"key":"ref62","doi-asserted-by":"publisher","first-page":"22235","DOI":"10.18632\/ONCOTARGET.14755","article-title":"RNA binding motif protein 3: a potential biomarker in cancer and therapeutic target in neuroprotection","volume":"8","author":"Zhou","year":"2017","journal-title":"Oncotarget"}],"container-title":["Frontiers in Aging Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2023.1290681\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,15]],"date-time":"2023-12-15T11:04:16Z","timestamp":1702638256000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2023.1290681\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,15]]},"references-count":64,"alternative-id":["10.3389\/fnagi.2023.1290681"],"URL":"https:\/\/doi.org\/10.3389\/fnagi.2023.1290681","relation":{},"ISSN":["1663-4365"],"issn-type":[{"value":"1663-4365","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,15]]},"article-number":"1290681"}}