Granulin loss of function in human mature brain organoids implicates astrocytes in TDP-43 pathology
Martina de Majo, Mark Koontz, Elise Marsan, Nir Salinas, Marina Ramsey, Yien–Ming Kuo, Kyounghee Seo, Huinan Li, Nina M. Dräger, Kun Leng, Santiago L. Gonzales, Michael Kurnellas, Yuichiro Miyaoka, Joseph R. Klim, Martin Kampmann, Michael E. Ward, Eric J. Huang, Erik M. Ullian
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.