Granulin Loss of Function in Human Mature Brain Organoids Implicates Astrocytes in TDP-43 Pathology

Loss of function (LoF) of Tar-binding protein 43 (TDP-43) and mislocalization, together with TDP-43-positive and hyperphosphorylated inclusions, are found in postmortem 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 3D-induced pluripotent stem cell (iPSC)-derived paradigm - mature brain organoids (mbOrg) - composed of cortical-like-astrocytes (iA) and neurons (iN). When devoid of GRN, mbOrgs spontaneously recapitulate TDP-43 mislocalization, 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 mechanistic modeling of TDP-43 pathology and patient-tailored therapeutic screening for FTD and ALS. ### Competing Interest Statement The authors have declared no competing interest.