{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T10:55:52Z","timestamp":1791456952050,"version":"4.3.4"},"reference-count":62,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:00:00Z","timestamp":1791417600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:00:00Z","timestamp":1791417600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100014440","name":"Ministerio de Ciencia, Innovaci\u00f3n y Universidades","doi-asserted-by":"publisher","award":["PID2022\u2010137238OB\u2010I00"],"award-info":[{"award-number":["PID2022\u2010137238OB\u2010I00"]}],"id":[{"id":"10.13039\/100014440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008054","name":"Fundaci\u00f3n Ram\u00f3n Areces","doi-asserted-by":"publisher","award":["CEX2021\u2010001154\u2010S"],"award-info":[{"award-number":["CEX2021\u2010001154\u2010S"]}],"id":[{"id":"10.13039\/100008054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Propionic acidemia (PA) is a neurometabolic disorder caused by propionyl\u2010CoA carboxylase deficiency with frequent neurological involvement, yet cell\u2010type\u2010specific mechanisms remain poorly defined. We established human induced pluripotent stem cell (iPSC)\u2010derived astrocytes (iAs) from patients harboring\n                    <jats:italic>PCCA<\/jats:italic>\n                    or\n                    <jats:italic>PCCB<\/jats:italic>\n                    mutations and investigated functional and molecular alterations associated with PA. Both control\u2010 and patient\u2010derived iPSCs yielded astrocyte\u2010enriched cultures through a neural progenitor intermediate, with expression of astrocyte\u2010associated markers. Patient iAs showed impaired mitochondrial respiration (lower basal and maximal oxygen consumption and ATP\u2010linked respiration), together with reduced high\u2010affinity uptake of glutamate and glycine neurotransmitters and evidence of disturbed Ca\n                    <jats:sup>2+<\/jats:sup>\n                    homeostasis. They also migrated faster in wound\u2010healing assays and displayed reactive\u2010like features, including increased GFAP and connexin 43 (Cx43) protein levels and elevated\n                    <jats:italic>AQP4<\/jats:italic>\n                    mRNA levels. Targeted miRNA profiling revealed upregulation of miR\u2010124\u20103p, miR\u20109\u20105p, and miR\u2010125b\u20105p, concomitant with downregulation of miR\u2010146a\u20105p, miR\u2010155\u20105p, and miR\u2010145\u20105p. Consistent with these changes, reported target genes associated with innate immune signaling (\n                    <jats:italic>IRAK1<\/jats:italic>\n                    ,\n                    <jats:italic>TRAF6<\/jats:italic>\n                    ,\n                    <jats:italic>TAB2<\/jats:italic>\n                    ), astrocyte remodeling (\n                    <jats:italic>GFAP<\/jats:italic>\n                    ), and water\/ion homeostasis (\n                    <jats:italic>AQP4<\/jats:italic>\n                    ) were upregulated. Inflammatory and proliferative markers were likewise increased, including\n                    <jats:italic>IL1B<\/jats:italic>\n                    ,\n                    <jats:italic>TNF<\/jats:italic>\n                    , and\n                    <jats:italic>MKI67<\/jats:italic>\n                    . Together, these convergent alterations suggest a phenotype characterized by impaired homeostatic functions and reactive\u2010like features, which may heighten neural network vulnerability under metabolic stress. Collectively, our data support astrocyte dysfunction as a potential contributor to PA neuropathology and highlight patient\u2010derived iAs as a useful model for future mechanistic studies and therapeutic exploration. \u00a9 2026 The Author(s).\n                    <jats:italic>The Journal of Pathology<\/jats:italic>\n                    published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.70140","type":"journal-article","created":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T10:33:12Z","timestamp":1791455592000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Patient\n                    <scp>iPSC<\/scp>\n                    \u2010derived astrocytes reveal impaired homeostasis and reactive\u2010like features in propionic acidemia"],"prefix":"10.1002","author":[{"given":"Irene","family":"Gonz\u00e1lez\u2010Garnacho","sequence":"first","affiliation":[{"name":"Centro de Biolog\u00eda Molecular Severo Ochoa UAM\u2010CSIC Universidad Aut\u00f3noma de Madrid  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar","family":"\u00c1lvarez","sequence":"additional","affiliation":[{"name":"Centro de Biolog\u00eda Molecular Severo Ochoa UAM\u2010CSIC Universidad Aut\u00f3noma de Madrid  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco","family":"Zafra","sequence":"additional","affiliation":[{"name":"Centro de Biolog\u00eda Molecular Severo Ochoa UAM\u2010CSIC Universidad Aut\u00f3noma de Madrid  Madrid Spain"},{"name":"Instituto Universitario de Biolog\u00eda Molecular (IUBM)  Madrid Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria Hospital La Paz (IdiPaz)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pilar","family":"Rodr\u00edguez\u2010Pombo","sequence":"additional","affiliation":[{"name":"Centro de Biolog\u00eda Molecular Severo Ochoa UAM\u2010CSIC Universidad Aut\u00f3noma de Madrid  Madrid Spain"},{"name":"Instituto Universitario de Biolog\u00eda Molecular (IUBM)  Madrid Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria Hospital La Paz (IdiPaz)  Madrid Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER) Instituto de Salud Carlos III (ISCIII)  Madrid Spain"},{"name":"Centro de Diagn\u00f3stico de Enfermedades Moleculares (CEDEM) Universidad Aut\u00f3noma de Madrid  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0492-3323","authenticated-orcid":false,"given":"Lourdes R","family":"Desviat","sequence":"additional","affiliation":[{"name":"Centro de Biolog\u00eda Molecular Severo Ochoa UAM\u2010CSIC Universidad Aut\u00f3noma de Madrid  Madrid Spain"},{"name":"Instituto Universitario de Biolog\u00eda Molecular (IUBM)  Madrid Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria Hospital La Paz (IdiPaz)  Madrid Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER) Instituto de Salud Carlos III (ISCIII)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9711-1417","authenticated-orcid":false,"given":"Eva","family":"Richard","sequence":"additional","affiliation":[{"name":"Centro de Biolog\u00eda Molecular Severo Ochoa UAM\u2010CSIC Universidad Aut\u00f3noma de Madrid  Madrid Spain"},{"name":"Instituto Universitario de Biolog\u00eda Molecular (IUBM)  Madrid Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria Hospital La Paz (IdiPaz)  Madrid Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER) Instituto de Salud 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