{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T20:16:32Z","timestamp":1790885792922,"version":"4.1.0"},"reference-count":89,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T00:00:00Z","timestamp":1757635200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100014076","name":"Stichting ALS Nederland","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100014076","id-type":"DOI","asserted-by":"publisher"}]},{"name":"MAXOMOD and INTEGRALS consortia"},{"name":"ERANet"},{"name":"ALS CURE project"},{"DOI":"10.13039\/501100010969","name":"Alzheimer Nederland","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100010969","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013278","name":"EU joint Program Neurodegenerative Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013278","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,3,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by loss of upper and lower motor neurons and progressive muscle wasting. Accumulating evidence indicates a role for non-neuronal cells in ALS pathogenesis, but their exact role and mechanism-of-action remain incompletely understood. A hexanucleotide (GGGGCC) repeat expansion (HRE) in C9ORF72 is the most common genetic cause of ALS (C9-ALS) and a frequent cause of frontotemporal dementia (FTD).<\/jats:p>\n                  <jats:p>Several lines of experimental evidence support a role for the immune system and microglia in C9-ALS\/FTD, and depending on experimental settings and species used, both reduced and increased microglial activity have been reported. To further study microglia in C9-ALS\/FTD in the context of a complex, 3D disease environment, we developed cerebral organoids that innately develop microglia derived from induced pluripotent stem cells (iPSCs) of C9-ALS\/FTD patients and controls.<\/jats:p>\n                  <jats:p>Here, we show reduced cellular complexity and transcriptional changes in C9 neural organoid-derived microglia (C9-oMGs), involving phagocytic, lysosomal and immune response pathways. The release of inflammatory cues from C9-ALS\/FTD organoids is decreased and LAMP1 expression in C9-oMGs is reduced. Functional analysis using live imaging reveals impaired phagocytosis by C9-oMGs and reduced engulfment of the post-synaptic protein PSD-95 by C9-oMGs in organoids. Finally, our transcriptomics analysis identifies a PU.1 (encoded by SPI1) regulon as the most strongly downregulated transcription factor network in C9-oMGs. Viral overexpression of PU.1 rescues phagocytosis and gene expression defects in C9-microglia.<\/jats:p>\n                  <jats:p>Overall, our data demonstrate reduced microglial functions in a complex cellular disease environment and identify PU.1 as a potential target for restoring microglia changes in C9-ALS\/FTD.<\/jats:p>","DOI":"10.1093\/brain\/awaf340","type":"journal-article","created":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T12:04:51Z","timestamp":1757678691000},"page":"801-817","source":"Crossref","is-referenced-by-count":3,"title":["PU.1 restores microglial dysfunction caused by C9ORF72 repeat expansions in neural organoids"],"prefix":"10.1093","volume":"149","author":[{"given":"Tijana","family":"Ljubikj","sequence":"first","affiliation":[{"name":"Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht University , Utrecht 3584 CG ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayte Z","family":"Mars","sequence":"additional","affiliation":[{"name":"Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht University , Utrecht 3584 CG ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astrid T","family":"van der Geest","sequence":"additional","affiliation":[{"name":"Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht University , Utrecht 3584 CG ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Channa E","family":"Jakobs","sequence":"additional","affiliation":[{"name":"Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht University , Utrecht 3584 CG ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nils","family":"Bessler","sequence":"additional","affiliation":[{"name":"Princess M\u00e1xima Center for Pedriatic Onocology , Utrecht University, Utrecht 3584 CS ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3152-2675","authenticated-orcid":false,"given":"Vanessa","family":"Donega","sequence":"additional","affiliation":[{"name":"Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht University , Utrecht 3584 CG ,","place":["The Netherlands"]},{"name":"Department of Anatomy and Neurosciences, Amsterdam UMC Location Vrije Universiteit Amsterdam , Amsterdam 1081 HV ,","place":["The Netherlands"]},{"name":"Amsterdam Neuroscience, Cellular and Molecular Mechanisms , Amsterdam 1081 HV ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xynthia P R M","family":"van den Oetelaar","sequence":"additional","affiliation":[{"name":"Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht University , Utrecht 3584 CG ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"de Wit","sequence":"additional","affiliation":[{"name":"Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht University , Utrecht 3584 CG ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1631-6440","authenticated-orcid":false,"given":"R Jeroen","family":"Pasterkamp","sequence":"additional","affiliation":[{"name":"Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht University , Utrecht 3584 CG ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,9,12]]},"reference":[{"key":"2026030512071220400_awaf340-B1","doi-asserted-by":"crossref","first-page":"2084","DOI":"10.1016\/S0140-6736(17)31287-4","article-title":"Amyotrophic lateral sclerosis","volume":"390","author":"van Es","year":"2017","journal-title":"The Lancet"},{"key":"2026030512071220400_awaf340-B2","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.neuron.2011.09.011","article-title":"Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS","volume":"72","author":"DeJesus-Hernandez","year":"2011","journal-title":"Neuron"},{"key":"2026030512071220400_awaf340-B3","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.neuron.2011.09.010","article-title":"A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD","volume":"72","author":"Renton","year":"2011","journal-title":"Neuron"},{"key":"2026030512071220400_awaf340-B4","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1038\/s41582-018-0047-2","article-title":"C9orf72-mediated ALS and FTD: Multiple pathways to disease","volume":"14","author":"Balendra","year":"2018","journal-title":"Nat Rev Neurol"},{"key":"2026030512071220400_awaf340-B5","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/s13024-022-00525-z","article-title":"The role of inflammation in neurodegeneration: Novel insights into the role of the immune system in C9orf72 HRE-mediated ALS\/FTD","volume":"17","author":"Masrori","year":"2022","journal-title":"Mol Neurodegener"},{"key":"2026030512071220400_awaf340-B6","doi-asserted-by":"crossref","first-page":"486","DOI":"10.3389\/fnins.2019.00486","article-title":"Astrocytes and microglia as potential contributors to the pathogenesis of C9orf72 repeat expansion-associated FTLD and 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