{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Lorenzini I"],"funding":["BLRD VA","NIA NIH HHS","NINDS NIH HHS"],"pagination":["1179796"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10279871"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["17"],"pubmed_abstract":["While motor and cortical neurons are affected in <i>C9orf72</i> amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), it remains largely unknown if and how non-neuronal cells induce or exacerbate neuronal damage. We differentiated <i>C9orf72</i> ALS/FTD patient-derived induced pluripotent stem cells into microglia (iPSC-MG) and examined their intrinsic phenotypes. Similar to iPSC motor neurons, <i>C9orf72</i> ALS/FTD iPSC-MG mono-cultures form G<sub>4</sub>C<sub>2</sub> repeat RNA foci, exhibit reduced C9orf72 protein levels, and generate dipeptide repeat proteins. Healthy control and <i>C9orf72</i> ALS/FTD iPSC-MG equally express microglial specific genes and perform microglial functions, including inflammatory cytokine release and phagocytosis of extracellular cargos, such as synthetic amyloid beta peptides and healthy human brain synaptoneurosomes. RNA sequencing analysis revealed select transcriptional changes of genes associated with neuroinflammation or neurodegeneration in diseased microglia yet no significant differentially expressed microglial-enriched genes. Moderate molecular and functional differences were observed in <i>C9orf72</i> iPSC-MG mono-cultures despite the presence of C9orf72 pathological features suggesting that a diseased microenvironment may be required to induce phenotypic changes in microglial cells and the associated neuronal dysfunction seen in C9orf72 ALS/FTD neurodegeneration."],"journal":["Frontiers in cellular neuroscience"],"pubmed_title":["Moderate intrinsic phenotypic alterations in <i>C9orf72</i> ALS/FTD iPSC-microglia despite the presence of C9orf72 pathological features."],"pmcid":["PMC10279871"],"funding_grant_id":["R01 NS097545","T32 NS082174","P30 AG019610","T32 NS007433","R01 NS101986","R21 NS119952","RF1 NS101986","R01 NS120331","I01 BX003625"],"pubmed_authors":["Lall D","Burciu C","Saul J","Donnelly CJ","Logemann A","Alsop E","Mota TA","Lorenzini I","Ichida J","Bustos LM","Tzioras M","Rabichow BE","Pevey R","Bowser R","Almeida S","Spires-Jones T","McQuade A","Rose J","Moore S","Blurton-Jones M","Marks M","Gendron TF","Levy J","Baloh RH","Hutchins E","Gittings LM","Sattler R","Singer M","Gao FB","Bhatia D","Van Keuren-Jensen K","Hung ST"],"additional_accession":[]},"is_claimable":false,"name":"Moderate intrinsic phenotypic alterations in <i>C9orf72</i> ALS/FTD iPSC-microglia despite the presence of C9orf72 pathological features.","description":"While motor and cortical neurons are affected in <i>C9orf72</i> amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), it remains largely unknown if and how non-neuronal cells induce or exacerbate neuronal damage. We differentiated <i>C9orf72</i> ALS/FTD patient-derived induced pluripotent stem cells into microglia (iPSC-MG) and examined their intrinsic phenotypes. Similar to iPSC motor neurons, <i>C9orf72</i> ALS/FTD iPSC-MG mono-cultures form G<sub>4</sub>C<sub>2</sub> repeat RNA foci, exhibit reduced C9orf72 protein levels, and generate dipeptide repeat proteins. Healthy control and <i>C9orf72</i> ALS/FTD iPSC-MG equally express microglial specific genes and perform microglial functions, including inflammatory cytokine release and phagocytosis of extracellular cargos, such as synthetic amyloid beta peptides and healthy human brain synaptoneurosomes. RNA sequencing analysis revealed select transcriptional changes of genes associated with neuroinflammation or neurodegeneration in diseased microglia yet no significant differentially expressed microglial-enriched genes. Moderate molecular and functional differences were observed in <i>C9orf72</i> iPSC-MG mono-cultures despite the presence of C9orf72 pathological features suggesting that a diseased microenvironment may be required to induce phenotypic changes in microglial cells and the associated neuronal dysfunction seen in C9orf72 ALS/FTD neurodegeneration.","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023","modification":"2026-04-12T23:13:24.108Z","creation":"2025-02-19T04:31:02.384Z"},"accession":"S-EPMC10279871","cross_references":{"pubmed":["37346371"],"doi":["10.3389/fncel.2023.1179796"]}}