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

Abstract

SummaryLoss 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). Modelling TDP-43 pathology has been challengingin vivoandin 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 ofGRN, mbOrgs spontaneously recapitulate TDP-43 mislocalization, hyperphosphorylation and LoF phenotypes. Mixing-and-matching genotypes in mbOrgs showed thatGRN−/−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 modelling of TDP-43 pathology and patient-tailored therapeutic screening for FTD and ALS.HighlightsGRN−/−iPSC-derived 3D paradigm (mbOrg) composed of mature cortical-like astrocytes and neurons recapitulates features of TDP-43 proteinopathyGRN−/−cortical-like astrocytes are necessary and sufficient for the development of the TDP-43 loss of function phenotype in mbOrg.A TDP-43 phenotype can be rescued in neurons by treating neuron and astrocyte co-cultures with progranulin full length protein.eTOC blurbIn this article, de Majo and colleagues present a novel 3D iPSC-derived model to study neurodegenerative disorders such as ALS and FTD. When devoid ofGRNexpression, these cultures present features of ALS and FTD associated pathology hardly ever observedin vitro. These phenotypes are shown to be primarily driven by diseased astrocytes and can be rescued by progranulin supplementation.