{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:20:04Z","timestamp":1787026804187,"version":"build-2736575974"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,9,5]],"date-time":"2024-09-05T00:00:00Z","timestamp":1725494400000},"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. Cell. Neurosci."],"abstract":"<jats:p>\n                    Coenzyme A (CoA), which is widely distributed and vital for cellular metabolism, is a critical molecule essential in both synthesizing and breaking down key energy sources in the body. Inborn errors of metabolism in the cellular\n                    <jats:italic>de novo<\/jats:italic>\n                    biosynthetic pathway of CoA have been linked to human genetic disorders, emphasizing the importance of this pathway. The\n                    <jats:italic>COASY<\/jats:italic>\n                    gene encodes the bifunctional enzyme CoA synthase, which catalyzes the last two reactions of the CoA biosynthetic pathway and serves as one of the rate-limiting components of the pathway. Recessive variants of this gene cause an exceptionally rare and devastating disease called COASY protein-associated neurodegeneration (CoPAN) while complete loss-of-function variants in\n                    <jats:italic>COASY<\/jats:italic>\n                    have been identified in fetuses\/neonates with Pontocerebellar Hypoplasia type 12 (PCH 12). Understanding why the different symptoms emerge in these disorders and what determines the development of one syndrome over the other is still not achieved. To shed light on the pathogenesis, we generated a new conditional animal model in which\n                    <jats:italic>Coasy<\/jats:italic>\n                    was deleted under the control of the human GFAP promoter. We used this mouse model to investigate how defects in the CoA biosynthetic pathway affect brain development. This model showed a broad spectrum of severity of the\n                    <jats:italic>in vivo<\/jats:italic>\n                    phenotype, ranging from very short survival (less than 2\u2009weeks) to normal life expectancy in some animals. Surviving mice displayed a behavioral phenotype with sensorimotor defects.\n                    <jats:italic>Ex vivo<\/jats:italic>\n                    histological analysis revealed variable but consistent cerebral and cerebellar cortical hypoplasia, in parallel with a broad astrocytic hyper-proliferation in the cerebral cortex. In addition, primary astrocytes derived from this model exhibited lipid peroxidation, iron dyshomeostasis, and impaired mitochondrial respiration. Notably,\n                    <jats:italic>Coasy<\/jats:italic>\n                    ablation in radial glia and astrocytic lineage triggers abnormal neuronal development and chronic neuroinflammation, offering new insights into disease mechanisms.\n                  <\/jats:p>","DOI":"10.3389\/fncel.2024.1458475","type":"journal-article","created":{"date-parts":[[2024,9,5]],"date-time":"2024-09-05T00:36:52Z","timestamp":1725496612000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["CoA synthase plays a critical role in neurodevelopment and neurodegeneration"],"prefix":"10.3389","volume":"18","author":[{"given":"Chiara","family":"Cavestro","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"D\u2019Amato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Nicol","family":"Colombo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Floriana","family":"Cascone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea Stefano","family":"Moro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Levi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Tiranti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivano","family":"Di Meo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,9,5]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1007\/s12098-023-04515-x","article-title":"Status epilepticus in coenzyme a synthase protein-associated neurodegeneration - expanding the clinical phenotype","volume":"90","author":"Ajit","year":"2023","journal-title":"Indian J. Pediatr."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1016\/j.celrep.2015.12.065","article-title":"NCOA4 deficiency impairs systemic Iron homeostasis","volume":"14","author":"Bellelli","year":"2016","journal-title":"Cell Rep."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1002\/jimd.12584","article-title":"Pathogenic variants of the coenzyme a biosynthesis-associated enzyme phosphopantothenoylcysteine decarboxylase cause autosomal-recessive dilated cardiomyopathy","volume":"46","author":"Bravo-Alonso","year":"2023","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1038\/nrn2652","article-title":"Tests to assess motor phenotype in mice: a user\u2019s guide","volume":"10","author":"Brooks","year":"2009","journal-title":"Nat. Rev. Neurosci."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1016\/j.bbabio.2004.09.006","article-title":"Clinical and molecular findings in children with complex I deficiency","volume":"1659","author":"Bugiani","year":"2004","journal-title":"Biochim. Biophys. Acta"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"5951","DOI":"10.3390\/ijms24065951","article-title":"Inherited disorders of coenzyme a biosynthesis: models, mechanisms, and treatments","volume":"24","author":"Cavestro","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"1615","DOI":"10.1002\/acn3.52079","article-title":"Emerging variants, unique phenotypes, and transcriptomic signatures: an integrated study of COASY-associated diseases","volume":"11","author":"Cavestro","year":"2024","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"126","DOI":"10.15698\/mic2015.04.196","article-title":"Modeling human coenzyme a synthase mutation in yeast reveals altered mitochondrial function, lipid content and iron metabolism","volume":"2","author":"Ceccatelli Berti","year":"2015","journal-title":"Microb. Cell"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"9707","DOI":"10.3390\/ijms21249707","article-title":"Neuronal ablation of CoA synthase causes motor deficits, Iron Dyshomeostasis, and mitochondrial dysfunctions in a CoPAN mouse model","volume":"21","author":"Di Meo","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.ajhg.2013.11.008","article-title":"Exome sequence reveals mutations in CoA synthase as a cause of neurodegeneration with brain iron accumulation","volume":"94","author":"Dusi","year":"2014","journal-title":"Am. J. Hum. Genet."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"1233","DOI":"10.1038\/nn1340","article-title":"GFAP-expressing progenitors are the principal source of constitutive neurogenesis in adult mouse forebrain","volume":"7","author":"Garcia","year":"2004","journal-title":"Nat. Neurosci."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1002\/mdc3.13624","article-title":"A mild form of neurodegeneration with brain Iron accumulation attributed to coenzyme a synthase mutation","volume":"10","author":"Hashemi","year":"2023","journal-title":"Mov. Disord. Clin. Pract."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.cell.2010.06.028","article-title":"Two to tango: regulation of mammalian iron metabolism","volume":"142","author":"Hentze","year":"2010","journal-title":"Cell"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"1018","DOI":"10.1016\/j.ajhg.2018.03.022","article-title":"Mutations in PPCS, encoding Phosphopantothenoylcysteine Synthetase, cause autosomal-recessive dilated cardiomyopathy","volume":"102","author":"Iuso","year":"2018","journal-title":"Am. J. Hum. Genet."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"3327","DOI":"10.1093\/hmg\/ddx217","article-title":"Mitochondrial dysfunction underlies cognitive defects as a result of neural stem cell depletion and impaired neurogenesis","volume":"26","author":"Khacho","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"37660","DOI":"10.1038\/srep37660","article-title":"Down-regulation of coasy, the gene associated with NBIA-VI, reduces bmp signaling, perturbs dorso-ventral patterning and alters neuronal development in zebrafish","volume":"6","author":"Khatri","year":"2016","journal-title":"Sci. Rep."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"1039","DOI":"10.1038\/s41467-018-03422-6","article-title":"CoA synthase regulates mitotic fidelity via CBP-mediated acetylation","volume":"9","author":"Lin","year":"2018","journal-title":"Nat. Commun."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"2783","DOI":"10.1002\/ajmg.a.62848","article-title":"Novel phosphopantothenoylcysteine synthetase (PPCS) mutations with prominent neuromuscular features: expanding the phenotypical spectrum of PPCS-related disorders","volume":"188","author":"Lok","year":"2022","journal-title":"Am. J. Med. Genet. 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Neurol."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1016\/S0896-6273(03)00116-8","article-title":"Neuronal or glial progeny: regional differences in radial glia fate","volume":"37","author":"Malatesta","year":"2003","journal-title":"Neuron"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1038\/nature13148","article-title":"Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy","volume":"509","author":"Mancias","year":"2014","journal-title":"Nature"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"2339","DOI":"10.1002\/ajmg.a.62768","article-title":"COASY related pontocerebellar hypoplasia type 12: a common Indian mutation with expansion of the phenotypic spectrum","volume":"188","author":"Mishra","year":"2022","journal-title":"Am. J. Med. Genet. A"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"408","DOI":"10.1016\/j.neuron.2020.11.014","article-title":"Metabolic regulation of neocortical expansion in development and evolution","volume":"109","author":"Namba","year":"2021","journal-title":"Neuron"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1111\/1567-1364.12058","article-title":"Molecular characterization of the heteromeric coenzyme A-synthesizing protein complex (CoA-SPC) in the yeast Saccharomyces cerevisiae","volume":"13","author":"Olzhausen","year":"2013","journal-title":"FEMS Yeast Res."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"680","DOI":"10.1002\/glia.20796","article-title":"Quality control of astrocyte-directed Cre transgenic mice: The benefits of a direct link between loss of gene expression and reporter activation","volume":"57","author":"Requardt","year":"2009","journal-title":"Glia"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"1328","DOI":"10.1126\/science.1230593","article-title":"Proteomic mapping of mitochondria in living cells via spatially restricted enzymatic tagging","volume":"339","author":"Rhee","year":"2013","journal-title":"Science"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"E1","DOI":"10.1152\/ajpendo.1985.248.1.E1","article-title":"Coenzyme a metabolism","volume":"248","author":"Robishaw","year":"1985","journal-title":"Am. 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Purif."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1038\/s41419-022-04626-x","article-title":"Massive iron accumulation in PKAN-derived neurons and astrocytes: light on the human pathological phenotype","volume":"13","author":"Santambrogio","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.pediatrneurol.2021.07.012","article-title":"Neurodevelopmental clues to neurodegeneration","volume":"123","author":"Schor","year":"2021","journal-title":"Pediatr. Neurol."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"267","DOI":"10.3389\/fncel.2016.00267","article-title":"Scale invariant disordered Nanotopography promotes hippocampal neuron development and maturation with involvement of Mechanotransductive pathways","volume":"10","author":"Schulte","year":"2016","journal-title":"Front. Cell. Neurosci."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"1075","DOI":"10.1042\/BST20140125","article-title":"Coenzyme a, more than \u201cjust\u201d a metabolic cofactor","volume":"42","author":"Srinivasan","year":"2014","journal-title":"Biochem. Soc. Trans."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"1752","DOI":"10.1038\/s41431-018-0233-0","article-title":"Biallelic loss of function variants in COASY cause prenatal onset pontocerebellar hypoplasia, microcephaly, and arthrogryposis","volume":"26","author":"van Dijk","year":"2018","journal-title":"Eur. J. Hum. Genet."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"267","DOI":"10.3390\/pharmaceutics15010267","article-title":"Identification of autophagy as a functional target suitable for the pharmacological treatment of mitochondrial membrane protein-associated neurodegeneration (MPAN) in vitro","volume":"15","author":"Zanuttigh","year":"2023","journal-title":"Pharmaceutics"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1038\/s41421-023-00641-0","article-title":"COASY variant as a new genetic cause of riboflavin-responsive lipid storage myopathy","volume":"10","author":"Zheng","year":"2024","journal-title":"Cell Discov."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1038\/ng572","article-title":"A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome","volume":"28","author":"Zhou","year":"2001","journal-title":"Nat. Genet."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1002\/gene.10008","article-title":"hGFAP-cre transgenic mice for manipulation of glial and neuronal function in vivo","volume":"31","author":"Zhuo","year":"2001","journal-title":"Genesis"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"50316","DOI":"10.1074\/jbc.M307763200","article-title":"Subcellular localization and regulation of coenzyme a synthase*","volume":"278","author":"Zhyvoloup","year":"2003","journal-title":"J. Biol. Chem."}],"container-title":["Frontiers in Cellular Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncel.2024.1458475\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,5]],"date-time":"2024-09-05T00:37:01Z","timestamp":1725496621000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncel.2024.1458475\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,5]]},"references-count":40,"alternative-id":["10.3389\/fncel.2024.1458475"],"URL":"https:\/\/doi.org\/10.3389\/fncel.2024.1458475","relation":{},"ISSN":["1662-5102"],"issn-type":[{"value":"1662-5102","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,5]]},"article-number":"1458475"}}