{"doi":"10.1016/j.stemcr.2023.01.012","title":"Granulin loss of function in human mature brain organoids implicates astrocytes in TDP-43 pathology","abstract":"Loss of function (LoF) of TAR-DNA binding protein 43 (TDP-43) and mis-localization, together with TDP-43-positive and hyperphosphorylated inclusions, are found in post-mortem tissue of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients, including those carrying LoF variants in the progranulin gene ( GRN ). Modeling TDP-43 pathology has been challenging in vivo and in vitro . We present a three-dimensional induced pluripotent stem cell (iPSC)-derived paradigm—mature brain organoids (mbOrg)—composed of cortical-like-astrocytes (iA) and neurons. When devoid of GRN , mbOrgs spontaneously recapitulate TDP-43 mis-localization, hyperphosphorylation, and LoF phenotypes. Mixing and matching genotypes in mbOrgs showed that GRN −/− iA are drivers for TDP-43 pathology. Finally, we rescued TDP-43 LoF by adding exogenous progranulin, demonstrating a link between TDP-43 LoF and progranulin expression. In conclusion, we present an iPSC-derived platform that shows striking features of human TDP-43 proteinopathy and provides a tool for the mechanistic modeling of TDP-43 pathology and patient-tailored therapeutic screening for FTD and ALS.","journal":"Stem Cell Reports","year":2023,"id":321346,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":44,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9639,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":255918,"name":"Mark Koontz","orcid":"0000-0001-5390-9515","position":1,"is_corresponding":false},{"id":975793,"name":"Elise Marsan","orcid":"0000-0003-1975-290X","position":2,"is_corresponding":false},{"id":708622,"name":"Nir Salinas","orcid":"0000-0002-3511-2243","position":3,"is_corresponding":false},{"id":368355,"name":"Marina Ramsey","orcid":"0000-0002-5870-812X","position":4,"is_corresponding":false},{"id":672515,"name":"Yien–Ming Kuo","orcid":"0000-0001-9925-3013","position":5,"is_corresponding":false},{"id":257255,"name":"Kyounghee Seo","orcid":null,"position":6,"is_corresponding":false},{"id":998682,"name":"Huinan Li","orcid":null,"position":7,"is_corresponding":false},{"id":553161,"name":"Nina M. Dräger","orcid":null,"position":8,"is_corresponding":false},{"id":552201,"name":"Kun Leng","orcid":"0000-0001-9931-1375","position":9,"is_corresponding":false},{"id":998683,"name":"Santiago L. Gonzales","orcid":null,"position":10,"is_corresponding":false},{"id":998086,"name":"Michael Kurnellas","orcid":"0000-0002-1264-6672","position":11,"is_corresponding":false},{"id":404059,"name":"Yuichiro Miyaoka","orcid":"0000-0002-8874-4738","position":12,"is_corresponding":false},{"id":652137,"name":"Joseph R. Klim","orcid":"0000-0001-8119-2144","position":13,"is_corresponding":false},{"id":218683,"name":"Martin Kampmann","orcid":"0000-0002-3819-7019","position":14,"is_corresponding":false},{"id":225567,"name":"Michael E. Ward","orcid":"0000-0002-5296-8051","position":15,"is_corresponding":false},{"id":226820,"name":"Eric J. Huang","orcid":"0000-0002-5381-3801","position":16,"is_corresponding":false},{"id":226822,"name":"Erik M. Ullian","orcid":"0000-0003-2077-8584","position":17,"is_corresponding":false},{"id":844150,"name":"Martina de Majo","orcid":"0000-0003-4524-6293","position":0,"is_corresponding":true}],"reference_count":71,"raw_metadata":null,"created_at":"2026-07-19T01:07:32.611759Z","pmid":"36827976","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}