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Stem Cell Reports. 2017 Mar 14;8(3):648-658. doi: 10.1016/j.stemcr.2017.01.012. Epub 2017 Feb 16.

Patient iPSC-Derived Neurons for Disease Modeling of Frontotemporal Dementia with Mutation in CHMP2B.

Author information

1
Stem Cells and Embryology Group, Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg C, Denmark. Electronic address: yu.zhang@sund.ku.dk.
2
Bioneer A/S, 2970 Hørsholm, Denmark.
3
Stem Cells and Embryology Group, Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg C, Denmark.
4
Neurometabolism Research Unit, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark.
5
Stem Cell and Developmental Neurobiology Group, Department of Neurobiology Research, University of Southern Denmark, 5000 Odense C, Denmark.
6
The Physiology Group, Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg C, Denmark.
7
H. Lundbeck A/S, 2500 Valby, Denmark.
8
Neurogenetics Clinic & Research Lab, Danish Dementia Research Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
9
BGI-Shenzhen, 518083 Shenzhen, China; China National GeneBank-Shenzhen, BGI-Shenzhen, 518083 Shenzhen, China.
10
Danish Regenerative Engineering Alliance for Medicine (DREAM), Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark.
11
Stem Cells and Embryology Group, Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg C, Denmark. Electronic address: kkf@sund.ku.dk.

Abstract

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.

KEYWORDS:

CHMP2B; disease modeling; endosome; frontotemporal dementia linked to chromosome 3 (FTD3); iPSC-derived neuron; iron homeostasis; mitochondria; neurodegeneration; oxidative stress

PMID:
28216144
PMCID:
PMC5355623
DOI:
10.1016/j.stemcr.2017.01.012
[Indexed for MEDLINE]
Free PMC Article

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