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Induced pluripotent stem cell models of progranulin-deficient frontotemporal dementia uncover specific reversible neuronal defects.

  • Author(s): 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
  • et al.

Published Web Location

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3532907/pdf/nihms-408994.pdf
No data is associated with this publication.
Abstract

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.

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