Induced pluripotent stem cell models of progranulin-deficient frontotemporal dementia uncover specific reversible neuronal defects.
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.
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Sandra
S
Almeida
Zhijun
Z
Zhang
Giovanni
G
Coppola
Wenjie
W
Mao
Kensuke
K
Futai
Anna
A
Karydas
Michael D
MD
Geschwind
M Carmela
MC
Tartaglia
Fuying
F
Gao
Davide
D
Gianni
Miguel
M
Sena-Esteves
Daniel H
DH
Geschwind
Bruce L
BL
Miller
Robert V
RV
Farese
Fen-Biao
FB
Gao
D002460:Cell Line; D015536:Down-Regulation; D057180:Frontotemporal Dementia / Q000378:metabolism* / Q000473:pathology; D057895:Haploinsufficiency; D006579:Heterozygote; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017628:Microglia / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000077153:Progranulins; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology
C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D047428:Protein Kinase Inhibitors; D058539:Phosphatidylinositol 3-Kinase; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020928:Mitogen-Activated Protein Kinases; D019311:Staurosporine