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While recent transcriptomic studies reveal profound glial and neuronal pathology in FTLD-GRN at the disease end stage, the mechanism that disrupts glia-neuron homeostasis remains unclear. Using induced pluripotent stem cell\u2013derived cortical organoids, we showed that\n                    <jats:italic>\n                      GRN\n                      <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    and\n                    <jats:italic>\n                      GRN\n                      <jats:sup>R493X<\/jats:sup>\n                    <\/jats:italic>\n                    mutations led to precocious astrogliosis that promoted neuronal stress and synaptic loss. Single-cell transcriptomics and histopathology analyses revealed a robust activation in the TGF-\u03b2 signaling pathway in\n                    <jats:italic>\n                      GRN\n                      <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    and\n                    <jats:italic>\n                      GRN\n                      <jats:sup>R493X\/R493X<\/jats:sup>\n                    <\/jats:italic>\n                    astrocytes, which was accompanied by features of immune activation, loss of synaptic support, and abundant pTDP-43\n                    <jats:sup>+<\/jats:sup>\n                    fibrils in astroglial cytoplasm, a feature characteristic of FTLD-GRN. Intriguingly, blocking TGF-\u03b2 signaling mitigated astroglial activation and pTDP-43 proteinopathy in\n                    <jats:italic>\n                      GRN\n                      <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    organoids. Together, these results provide insights into the cell-autonomous role of astroglial activation in neurodegeneration caused by progranulin deficiency.\n                  <\/jats:p>","DOI":"10.1172\/jci190035","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T23:01:53Z","timestamp":1781650913000},"source":"Crossref","is-referenced-by-count":0,"title":["TGF-\u03b2 signaling promotes astroglial activation and TDP-43 proteinopathy in organoid models of frontotemporal lobar degeneration"],"prefix":"10.1172","volume":"136","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5870-812X","authenticated-orcid":true,"given":"Arren C.","family":"Ramsey","sequence":"first","affiliation":[{"name":"Department of Pathology,"},{"name":"BMS Graduate Program, and"},{"name":"Weill Institute for Neurosciences, UCSF, San Francisco, California, 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