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Patient iPSC-Derived Neurons for Disease Modeling of Frontotemporal Dementia with Mutation in CHMP2B.
- Source :
-
Stem cell reports [Stem Cell Reports] 2017 Mar 14; Vol. 8 (3), pp. 648-658. Date of Electronic Publication: 2017 Feb 16. - Publication Year :
- 2017
-
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.<br /> (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Cell Differentiation
Cellular Reprogramming
Endosomes metabolism
Fibroblasts cytology
Fibroblasts metabolism
Gene Expression Profiling
Humans
Iron metabolism
Mitochondria genetics
Mitochondria metabolism
Neurons cytology
Oxidative Stress genetics
Transcriptome
Endosomal Sorting Complexes Required for Transport genetics
Frontotemporal Dementia genetics
Induced Pluripotent Stem Cells cytology
Induced Pluripotent Stem Cells metabolism
Mutation
Neurons metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2213-6711
- Volume :
- 8
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Stem cell reports
- Publication Type :
- Academic Journal
- Accession number :
- 28216144
- Full Text :
- https://doi.org/10.1016/j.stemcr.2017.01.012