Induced Pluripotent Stem Cell Models of Progranulin-Deficient Frontotemporal Dementia Uncover Specific Reversible Neuronal Defects

• Published in: Cell reports (Cambridge) 2012-10, Vol.2 (4), p.789-798
• Main Authors: Almeida, Sandra, Zhang, Zhijun, Coppola, Giovanni, Mao, Wenjie, Futai, Kensuke, Karydas, Anna, Geschwind, Michael D., Tartaglia, M. Carmela, Gao, Fuying, Gianni, Davide, Sena-Esteves, Miguel, Geschwind, Daniel H., Miller, Bruce L., Farese, Robert V., Gao, Fen-Biao
• Format: Article
• Language: English
• Subjects: Cell Line; Down-Regulation; Frontotemporal Dementia - metabolism; Frontotemporal Dementia - pathology; Haploinsufficiency; Heterozygote; Humans; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - metabolism; Intercellular Signaling Peptides and Proteins - deficiency; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Microglia - metabolism; Mitogen-Activated Protein Kinases - metabolism; Mutation; Neurons - drug effects; Neurons - metabolism; Phosphatidylinositol 3-Kinase - metabolism; Progranulins; Protein Kinase Inhibitors - pharmacology; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; Staurosporine - pharmacology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2012.09.007

The pathogenic mechanisms of frontotemporal dementia (FTD) remain poorly understood. Here we generated multiple induced pluripotent stem cell lines from a control subject, a patient with sporadic FTD, and an FTD patient with a novel heterozygous GRN mutation (progranulin [PGRN] S116X). In neurons and microglia differentiated from PGRN S116X induced pluripotent stem cells, the levels of intracellular and secreted PGRN were reduced, establishing patient-specific cellular models of PGRN haploinsufficiency. Through a systematic screen of inducers of cellular stress, we found that PGRN S116X neurons, but not sporadic FTD neurons, exhibited increased sensitivity to staurosporine and other kinase inhibitors. Moreover, the serine/threonine kinase S6K2, a component of the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways, was specifically downregulated in PGRN S116X neurons. Both increased sensitivity to kinase inhibitors and reduced S6K2 were rescued by PGRN expression. Our findings identify cell-autonomous, reversible defects in patient neurons with PGRN deficiency, and provide a compelling model for studying PGRN-dependent pathogenic mechanisms and testing potential therapies. [Display omitted] ► A human neuron model of progranulin (PGRN) haploinsufficiency is established ► Sporadic and PGRN-deficient frontotemporal dementia patient iPSCs are made ► PGRN S116X mutant neurons are sensitive to stress by kinase inhibitors ► S6K2 is downregulated in patient neurons in a PGRN-dependent manner Progranulin (PGRN) mutations are a common cause of frontotemporal dementia, but the underlying molecular mechanism is unknown. Gao and colleagues now generate multiple frontotemporal dementia patient-specific induced pluripotent stem cell lines and establish a human neuronal model of PGRN haploinsufficiency. Studies on human postmitotic neurons derived from these lines reveal cell-autonomous and reversible defects in specific signaling pathways that are compromised in PGRN-deficient neurons and establish a model system for studying PGRN-dependent pathogenic mechanisms and testing potential therapies.