{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T19:06:03Z","timestamp":1791918363248,"version":"4.3.4"},"reference-count":55,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,6,4]],"date-time":"2022-06-04T00:00:00Z","timestamp":1654300800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100002243","name":"National Ataxia Foundation and Friedreich\u2019s Ataxia Research Alliance","doi-asserted-by":"publisher","award":["821396"],"award-info":[{"award-number":["821396"]}],"id":[{"id":"10.13039\/100002243","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Friedreich\u2019s ataxia (FRDA) is a rare genetic disorder caused by mutations in the gene frataxin, encoding for a mitochondrial protein involved in iron handling and in the biogenesis of iron\u2212sulphur clusters, and leading to progressive nervous system damage. Although the overt manifestations of FRDA in the nervous system are mainly observed in the neurons, alterations in non-neuronal cells may also contribute to the pathogenesis of the disease, as recently suggested for other neurodegenerative disorders. In FRDA, the involvement of glial cells can be ascribed to direct effects caused by frataxin loss, eliciting different aberrant mechanisms. Iron accumulation, mitochondria dysfunction, and reactive species overproduction, mechanisms identified as etiopathogenic in neurons in FRDA, can similarly affect glial cells, leading them to assume phenotypes that can concur to and exacerbate neuron loss. Recent findings obtained in FRDA patients and cellular and animal models of the disease have suggested that neuroinflammation can accompany and contribute to the neuropathology. In this review article, we discuss evidence about the involvement of neuroinflammatory-related mechanisms in models of FRDA and provide clues for the modulation of glial-related mechanisms as a possible strategy to improve disease features.<\/jats:p>","DOI":"10.3390\/ijms23116297","type":"journal-article","created":{"date-parts":[[2022,6,4]],"date-time":"2022-06-04T09:42:32Z","timestamp":1654335752000},"page":"6297","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Neuroinflammation in Friedreich\u2019s Ataxia"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5782-1665","authenticated-orcid":false,"given":"Savina","family":"Apolloni","sequence":"first","affiliation":[{"name":"Department of Biology, Tor Vergata University of Rome, 00133 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Milani","sequence":"additional","affiliation":[{"name":"Department of Biology, Tor Vergata University of Rome, 00133 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6646-7653","authenticated-orcid":false,"given":"Nadia","family":"D\u2019Ambrosi","sequence":"additional","affiliation":[{"name":"Department of Biology, Tor Vergata University of Rome, 00133 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,4]]},"reference":[{"key":"ref_1","unstructured":"Williams, C.T., and De Jesus, O. (2022). Friedreich Ataxia. StatPearls, StatPearls Publishing."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"838335","DOI":"10.3389\/fnins.2022.838335","article-title":"Recent Advances in the Elucidation of Frataxin Biochemical Function Open Novel Perspectives for the Treatment of Friedreich\u2019s Ataxia","volume":"16","author":"Monfort","year":"2022","journal-title":"Front. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2210","DOI":"10.1038\/s41467-019-09989-y","article-title":"Structure of the Human Frataxin-Bound Iron-Sulfur Cluster Assembly Complex Provides Insight into Its Activation Mechanism","volume":"10","author":"Fox","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"9276","DOI":"10.1074\/jbc.RA119.007716","article-title":"Mechanism of Frataxin \u201cBypass\u201d in Human Iron-Sulfur Cluster Biosynthesis with Implications for Friedreich\u2019s Ataxia","volume":"294","author":"Das","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"75","DOI":"10.3389\/fnins.2019.00075","article-title":"The Role of Iron in Friedreich\u2019s Ataxia: Insights From Studies in Human Tissues and Cellular and Animal Models","volume":"13","author":"Llorens","year":"2019","journal-title":"Front. Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"720658","DOI":"10.4061\/2011\/720658","article-title":"Iron and Mechanisms of Neurotoxicity","volume":"2011","author":"Salvador","year":"2010","journal-title":"Int. J. Alzheimers Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1089\/ars.2009.3015","article-title":"Friedreich Ataxia: Molecular Mechanisms, Redox Considerations, and Therapeutic Opportunities","volume":"13","author":"Santos","year":"2010","journal-title":"Antioxid. Redox Signal."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1226","DOI":"10.1089\/hum.2020.264","article-title":"Central Nervous System Therapeutic Targets in Friedreich Ataxia","volume":"31","author":"Harding","year":"2020","journal-title":"Hum. Gene Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1126\/science.aag2590","article-title":"How Neuroinflammation Contributes to Neurodegeneration","volume":"353","author":"Ransohoff","year":"2016","journal-title":"Science"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1007\/s00401-009-0589-x","article-title":"The Dorsal Root Ganglion in Friedreich\u2019s Ataxia","volume":"118","author":"Koeppen","year":"2009","journal-title":"Acta Neuropathol."},{"key":"ref_11","first-page":"1052","article-title":"Frataxin Deficiency Induces Schwann Cell Inflammation and Death. Biochim","volume":"1792","author":"Lu","year":"2009","journal-title":"Biophys. Acta"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"740","DOI":"10.3389\/fnins.2018.00740","article-title":"The Dual Role of Hepcidin in Brain Iron Load and Inflammation","volume":"12","author":"Vela","year":"2018","journal-title":"Front. Neurosci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1161\/CIRCULATIONAHA.116.021881","article-title":"Toll-Like Receptor 4\/MyD88-Mediated Signaling of Hepcidin Expression Causing Brain Iron Accumulation, Oxidative Injury, and Cognitive Impairment After Intracerebral Hemorrhage","volume":"134","author":"Xiong","year":"2016","journal-title":"Circulation"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Silva, A.M.N., and Rangel, M. (2022). The (Bio)Chemistry of Non-Transferrin-Bound Iron. Molecules, 27.","DOI":"10.3390\/molecules27061784"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1016\/S1474-4422(14)70117-6","article-title":"The Role of Iron in Brain Ageing and Neurodegenerative Disorders","volume":"13","author":"Ward","year":"2014","journal-title":"Lancet Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.bbagen.2011.10.016","article-title":"Functional Roles of Transferrin in the Brain","volume":"1820","author":"Leitner","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Urrutia, P.J., B\u00f3rquez, D.A., and N\u00fa\u00f1ez, M.T. (2021). Inflaming the Brain with Iron. Antioxidants, 10.","DOI":"10.3390\/antiox10010061"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1038\/s41582-019-0227-8","article-title":"Neuroinflammation\u2014A Common Thread in Neurological Disorders","volume":"15","author":"Gilhus","year":"2019","journal-title":"Nat. Rev. Neurol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1038\/nn.4338","article-title":"A Polarizing Question: Do M1 and M2 Microglia Exist?","volume":"19","author":"Ransohoff","year":"2016","journal-title":"Nat. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1089\/ars.2017.7271","article-title":"Neuroinflammation in Amyotrophic Lateral Sclerosis: Role of Redox (Dys)Regulation","volume":"29","author":"Cozzolino","year":"2018","journal-title":"Antioxid. Redox Signal."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/s12974-019-1430-7","article-title":"Iron Accentuated Reactive Oxygen Species Release by NADPH Oxidase in Activated Microglia Contributes to Oxidative Stress in Vitro","volume":"16","author":"Yauger","year":"2019","journal-title":"J. Neuroinflamm."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Simpson, D.S.A., and Oliver, P.L. (2020). ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease. Antioxidants, 9.","DOI":"10.3390\/antiox9080743"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"592","DOI":"10.3390\/antiox3030592","article-title":"Friedreich\u2019s Ataxia: A Neuronal Point of View on the Oxidative Stress Hypothesis","volume":"3","author":"Carletti","year":"2014","journal-title":"Antioxidants"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Rosito, M., Testi, C., Parisi, G., Cortese, B., Baiocco, P., and Di Angelantonio, S. (2020). Exploring the Use of Dimethyl Fumarate as Microglia Modulator for Neurodegenerative Diseases Treatment. Antioxidants, 9.","DOI":"10.3390\/antiox9080700"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Nnah, I.C., and Wessling-Resnick, M. (2018). Brain Iron Homeostasis: A Focus on Microglial Iron. Pharmaceuticals, 11.","DOI":"10.3390\/ph11040129"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1007\/s00210-020-01963-6","article-title":"Deferasirox, a Trivalent Iron Chelator, Ameliorates Neuronal Damage in Hemorrhagic Stroke Models","volume":"394","author":"Imai","year":"2021","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.neuroscience.2019.10.041","article-title":"Dimethyl Fumarate Reduces Microglia Functional Response to Tissue Damage and Favors Brain Iron Homeostasis","volume":"439","author":"Pagani","year":"2020","journal-title":"Neuroscience"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1038\/s41582-019-0184-2","article-title":"The Pro-Remyelination Properties of Microglia in the Central Nervous System","volume":"15","author":"Lloyd","year":"2019","journal-title":"Nat. Rev. Neurol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"eabk1131","DOI":"10.1126\/sciadv.abk1131","article-title":"Regulation of Myelination by Microglia","volume":"7","author":"Santos","year":"2021","journal-title":"Sci. Adv."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1016\/j.tins.2009.08.002","article-title":"Molecular Dissection of Reactive Astrogliosis and Glial Scar Formation","volume":"32","author":"Sofroniew","year":"2009","journal-title":"Trends Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.freeradbiomed.2020.07.012","article-title":"Astrocyte Hepcidin Ameliorates Neuronal Loss through Attenuating Brain Iron Deposition and Oxidative Stress in APP\/PS1 Mice","volume":"158","author":"Xu","year":"2020","journal-title":"Free Radic. Biol. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1038\/s41420-020-00346-3","article-title":"Hepcidin Overexpression in Astrocytes Alters Brain Iron Metabolism and Protects against Amyloid-\u03b2 Induced Brain Damage in Mice","volume":"6","author":"Zhang","year":"2020","journal-title":"Cell Death Discov."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"NS20200093","DOI":"10.1042\/NS20200093","article-title":"Mitochondrial and Metabolic Dysfunction in Friedreich Ataxia: Update on Pathophysiological Relevance and Clinical Interventions","volume":"5","author":"Lynch","year":"2021","journal-title":"Neuronal Signal."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1002\/mds.28825","article-title":"Neuroinflammation in the Cerebellum and Brainstem in Friedreich Ataxia: An [18F]-FEMPA PET Study","volume":"37","author":"Khan","year":"2022","journal-title":"Mov. Disord."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1007\/s00401-007-0220-y","article-title":"The Dentate Nucleus in Friedreich\u2019s Ataxia: The Role of Iron-Responsive Proteins","volume":"114","author":"Koeppen","year":"2007","journal-title":"Acta Neuropathol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1186\/s40478-016-0326-3","article-title":"Purkinje Cell Injury, Structural Plasticity and Fusion in Patients with Friedreich\u2019s Ataxia","volume":"4","author":"Kemp","year":"2016","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.mcn.2017.02.008","article-title":"A Role for Astrocytes in Cerebellar Deficits in Frataxin Deficiency: Protection by Insulin-like Growth Factor I","volume":"80","author":"Franco","year":"2017","journal-title":"Mol. Cell Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1007\/s12311-012-0383-5","article-title":"Friedreich\u2019s Ataxia Causes Redistribution of Iron, Copper, and Zinc in the Dentate Nucleus","volume":"11","author":"Koeppen","year":"2012","journal-title":"Cerebellum"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"eaaj2347","DOI":"10.1126\/scitranslmed.aaj2347","article-title":"Transplantation of Wild-Type Mouse Hematopoietic Stem and Progenitor Cells Ameliorates Deficits in a Mouse Model of Friedreich\u2019s Ataxia","volume":"9","author":"Rocca","year":"2017","journal-title":"Sci. Transl. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1002\/ana.24846","article-title":"Cytokine Therapy-Mediated Neuroprotection in a Friedreich\u2019s Ataxia Mouse Model","volume":"81","author":"Kemp","year":"2017","journal-title":"Ann. Neurol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"6838","DOI":"10.1093\/hmg\/ddu407","article-title":"Frataxin Deficiency Increases Cyclooxygenase 2 and Prostaglandins in Cell and Animal Models of Friedreich\u2019s Ataxia","volume":"23","author":"Hayashi","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1186\/s12974-022-02442-w","article-title":"The Smoothened Agonist SAG Reduces Mitochondrial Dysfunction and Neurotoxicity of Frataxin-Deficient Astrocytes","volume":"19","author":"Loria","year":"2022","journal-title":"J. Neuroinflamm."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"569293","DOI":"10.3389\/fmolb.2020.569293","article-title":"Molecular Defects in Friedreich\u2019s Ataxia: Convergence of Oxidative Stress and Cytoskeletal Abnormalities","volume":"7","author":"Smith","year":"2020","journal-title":"Front. Mol. Biosci."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Shen, Y., McMackin, M.Z., Shan, Y., Raetz, A., David, S., and Cortopassi, G. (2016). Frataxin Deficiency Promotes Excess Microglial DNA Damage and Inflammation That Is Rescued by PJ34. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0151026"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2828","DOI":"10.1093\/hmg\/ddq183","article-title":"Altered Lipid Metabolism in a Drosophila Model of Friedreich\u2019s Ataxia","volume":"19","author":"Navarro","year":"2010","journal-title":"Hum. Mol. Genet."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.nbd.2014.12.017","article-title":"Frataxin Knockdown in Human Astrocytes Triggers Cell Death and the Release of Factors That Cause Neuronal Toxicity","volume":"76","year":"2015","journal-title":"Neurobiol. Dis."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.freeradbiomed.2015.03.014","article-title":"Mitoferrin Modulates Iron Toxicity in a Drosophila Model of Friedreich\u2019s Ataxia","volume":"85","author":"Navarro","year":"2015","journal-title":"Free Radic. Biol. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"366","DOI":"10.3389\/fncel.2018.00366","article-title":"Plasma Markers of Neurodegeneration Are Raised in Friedreich\u2019s Ataxia","volume":"12","author":"Zeitlberger","year":"2018","journal-title":"Front. Cell Neurosci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1093\/jnen\/nlx087","article-title":"Friedreich Ataxia: Developmental Failure of the Dorsal Root Entry Zone","volume":"76","author":"Koeppen","year":"2017","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Cerrato, V. (2020). Cerebellar Astrocytes: Much More Than Passive Bystanders In Ataxia Pathophysiology. J. Clin. Med., 9.","DOI":"10.3390\/jcm9030757"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Sandi, C., Sandi, M., Jassal, H., Ezzatizadeh, V., Anjomani-Virmouni, S., Al-Mahdawi, S., and Pook, M.A. (2014). Generation and Characterisation of Friedreich Ataxia YG8R Mouse Fibroblast and Neural Stem Cell Models. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0089488"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"973","DOI":"10.2174\/1389450118666170816124203","article-title":"Mitochondrial Aconitase in Neurodegenerative Disorders: Role of a Metabolism- Related Molecule in Neurodegeneration","volume":"19","author":"Khodagholi","year":"2018","journal-title":"Curr. Drug Targets"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/1750-1326-7-51","article-title":"Frataxin Deficiency Unveils Cell-Context Dependent Actions of Insulin-like Growth Factor I on Neurons","volume":"7","author":"Franco","year":"2012","journal-title":"Mol. Neurodegener."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"38","DOI":"10.3389\/fnmol.2018.00038","article-title":"Mitofusin-Dependent ER Stress Triggers Glial Dysfunction and Nervous System Degeneration in a Drosophila Model of Friedreich\u2019s Ataxia","volume":"11","author":"Edenharter","year":"2018","journal-title":"Front. Mol. Neurosci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"104606","DOI":"10.1016\/j.nbd.2019.104606","article-title":"Friedreich Ataxia-Pathogenesis and Implications for Therapies","volume":"132","author":"Delatycki","year":"2019","journal-title":"Neurobiol. Dis."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/11\/6297\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:24:29Z","timestamp":1760138669000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/11\/6297"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,4]]},"references-count":55,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["ijms23116297"],"URL":"https:\/\/doi.org\/10.3390\/ijms23116297","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,4]]}}}