TY - JOUR
T1 - Patient iPSC-derived neurons for disease modeling of frontotemporal dementia with mutation in CHMP2B
AU - Zhang, Yu
AU - Schmid, Benjamin
AU - Qas Younan, Nanett Kvist
AU - Rasmussen, Mikkel A.
AU - Garcia, Blanca Irene Aldana
AU - Agger, Mikkel
AU - Callø, Kirstine
AU - Stummann, Tina C.
AU - Larsen, Hjalte M.
AU - Nielsen, Troels T.
AU - Huang, Jinrong
AU - Xu, Fengping
AU - Liu, Xin
AU - Bolund, Lars
AU - Meyer, Morten
AU - Bak, Lasse Kristoffer
AU - Waagepetersen, Helle S.
AU - Luo, Yonglun
AU - Nielsen, Jørgen Erik
AU - Consortium, The FReJA
AU - Holst, Bjørn
AU - Clausen, Christian
AU - Hyttel, Poul
AU - Freude, Kristine
PY - 2017
Y1 - 2017
N2 - The truncated mutant form of the charged multivesicular body protein 2B (CHMP2B) is causative for frontotemporal dementia linked to chromosome 3 (FTD3). CHMP2B is a constituent of the endosomal sorting complex required for transport (ESCRT) and, when mutated, disrupts endosome-to-lysosome trafficking and substrate degradation. To understand the underlying molecular pathology, FTD3 patient induced pluripotent stem cells (iPSCs) were differentiated into forebrain-type cortical neurons. FTD3 neurons exhibited abnormal endosomes, as previously shown in patients. Moreover, mitochondria of FTD3 neurons displayed defective cristae formation, accompanied by deficiencies in mitochondrial respiration and increased levels of reactive oxygen. In addition, we provide evidence for perturbed iron homeostasis, presenting an in vitro patient-specific model to study the effects of iron accumulation in neurodegenerative diseases. All phenotypes observed in FTD3 neurons were rescued in CRISPR/Cas9-edited isogenic controls. These findings illustrate the relevance of our patient-specific in vitro models and open up possibilities for drug target development.
AB - The truncated mutant form of the charged multivesicular body protein 2B (CHMP2B) is causative for frontotemporal dementia linked to chromosome 3 (FTD3). CHMP2B is a constituent of the endosomal sorting complex required for transport (ESCRT) and, when mutated, disrupts endosome-to-lysosome trafficking and substrate degradation. To understand the underlying molecular pathology, FTD3 patient induced pluripotent stem cells (iPSCs) were differentiated into forebrain-type cortical neurons. FTD3 neurons exhibited abnormal endosomes, as previously shown in patients. Moreover, mitochondria of FTD3 neurons displayed defective cristae formation, accompanied by deficiencies in mitochondrial respiration and increased levels of reactive oxygen. In addition, we provide evidence for perturbed iron homeostasis, presenting an in vitro patient-specific model to study the effects of iron accumulation in neurodegenerative diseases. All phenotypes observed in FTD3 neurons were rescued in CRISPR/Cas9-edited isogenic controls. These findings illustrate the relevance of our patient-specific in vitro models and open up possibilities for drug target development.
U2 - 10.1016/j.stemcr.2017.01.012
DO - 10.1016/j.stemcr.2017.01.012
M3 - Journal article
C2 - 28216144
VL - 8
SP - 648
EP - 658
JO - Stem Cell Reports
JF - Stem Cell Reports
SN - 2213-6711
IS - 3
ER -