Patient iPSC-Derived Neurons for Disease Modeling of Frontotemporal Dementia with Mutation in CHMP2B
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 traffickin...
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Elsevier
2017-03-01
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| Series: | Stem Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213671117300279 |
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| author | Yu Zhang Benjamin Schmid Nanett K. Nikolaisen Mikkel A. Rasmussen Blanca I. Aldana Mikkel Agger Kirstine Calloe Tina C. Stummann Hjalte M. Larsen Troels T. Nielsen Jinrong Huang Fengping Xu Xin Liu Lars Bolund Morten Meyer Lasse K. Bak Helle S. Waagepetersen Yonglun Luo Jørgen E. Nielsen Bjørn Holst Christian Clausen Poul Hyttel Kristine K. Freude |
| author_facet | Yu Zhang Benjamin Schmid Nanett K. Nikolaisen Mikkel A. Rasmussen Blanca I. Aldana Mikkel Agger Kirstine Calloe Tina C. Stummann Hjalte M. Larsen Troels T. Nielsen Jinrong Huang Fengping Xu Xin Liu Lars Bolund Morten Meyer Lasse K. Bak Helle S. Waagepetersen Yonglun Luo Jørgen E. Nielsen Bjørn Holst Christian Clausen Poul Hyttel Kristine K. Freude |
| author_sort | Yu Zhang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T03:55:54Z |
| format | Article |
| id | doaj.art-ddcff1aabf094e94bc737b7fbb9ee240 |
| institution | Directory Open Access Journal |
| issn | 2213-6711 |
| language | English |
| last_indexed | 2024-12-22T03:55:54Z |
| publishDate | 2017-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Stem Cell Reports |
| spelling | doaj.art-ddcff1aabf094e94bc737b7fbb9ee2402022-12-21T18:39:52ZengElsevierStem Cell Reports2213-67112017-03-018364865810.1016/j.stemcr.2017.01.012Patient iPSC-Derived Neurons for Disease Modeling of Frontotemporal Dementia with Mutation in CHMP2BYu Zhang0Benjamin Schmid1Nanett K. Nikolaisen2Mikkel A. Rasmussen3Blanca I. Aldana4Mikkel Agger5Kirstine Calloe6Tina C. Stummann7Hjalte M. Larsen8Troels T. Nielsen9Jinrong Huang10Fengping Xu11Xin Liu12Lars Bolund13Morten Meyer14Lasse K. Bak15Helle S. Waagepetersen16Yonglun Luo17Jørgen E. Nielsen18Bjørn Holst19Christian Clausen20Poul Hyttel21Kristine K. Freude22Stem Cells and Embryology Group, Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg C, DenmarkBioneer A/S, 2970 Hørsholm, DenmarkStem Cells and Embryology Group, Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg C, DenmarkBioneer A/S, 2970 Hørsholm, DenmarkNeurometabolism Research Unit, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, DenmarkStem Cell and Developmental Neurobiology Group, Department of Neurobiology Research, University of Southern Denmark, 5000 Odense C, DenmarkThe Physiology Group, Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg C, DenmarkH. Lundbeck A/S, 2500 Valby, DenmarkStem Cells and Embryology Group, Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg C, DenmarkNeurogenetics Clinic & Research Lab, Danish Dementia Research Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, DenmarkBGI-Shenzhen, 518083 Shenzhen, ChinaBGI-Shenzhen, 518083 Shenzhen, ChinaBGI-Shenzhen, 518083 Shenzhen, ChinaDanish Regenerative Engineering Alliance for Medicine (DREAM), Department of Biomedicine, Aarhus University, 8000 Aarhus C, DenmarkStem Cell and Developmental Neurobiology Group, Department of Neurobiology Research, University of Southern Denmark, 5000 Odense C, DenmarkNeurometabolism Research Unit, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, DenmarkNeurometabolism Research Unit, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, DenmarkDanish Regenerative Engineering Alliance for Medicine (DREAM), Department of Biomedicine, Aarhus University, 8000 Aarhus C, DenmarkNeurogenetics Clinic & Research Lab, Danish Dementia Research Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, DenmarkBioneer A/S, 2970 Hørsholm, DenmarkBioneer A/S, 2970 Hørsholm, DenmarkStem Cells and Embryology Group, Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg C, DenmarkStem Cells and Embryology Group, Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg C, DenmarkThe 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.http://www.sciencedirect.com/science/article/pii/S2213671117300279frontotemporal dementia linked to chromosome 3 (FTD3)CHMP2BiPSC-derived neurondisease modelingendosomemitochondriairon homeostasisoxidative stressneurodegeneration |
| spellingShingle | Yu Zhang Benjamin Schmid Nanett K. Nikolaisen Mikkel A. Rasmussen Blanca I. Aldana Mikkel Agger Kirstine Calloe Tina C. Stummann Hjalte M. Larsen Troels T. Nielsen Jinrong Huang Fengping Xu Xin Liu Lars Bolund Morten Meyer Lasse K. Bak Helle S. Waagepetersen Yonglun Luo Jørgen E. Nielsen Bjørn Holst Christian Clausen Poul Hyttel Kristine K. Freude Patient iPSC-Derived Neurons for Disease Modeling of Frontotemporal Dementia with Mutation in CHMP2B Stem Cell Reports frontotemporal dementia linked to chromosome 3 (FTD3) CHMP2B iPSC-derived neuron disease modeling endosome mitochondria iron homeostasis oxidative stress neurodegeneration |
| title | Patient iPSC-Derived Neurons for Disease Modeling of Frontotemporal Dementia with Mutation in CHMP2B |
| title_full | Patient iPSC-Derived Neurons for Disease Modeling of Frontotemporal Dementia with Mutation in CHMP2B |
| title_fullStr | Patient iPSC-Derived Neurons for Disease Modeling of Frontotemporal Dementia with Mutation in CHMP2B |
| title_full_unstemmed | Patient iPSC-Derived Neurons for Disease Modeling of Frontotemporal Dementia with Mutation in CHMP2B |
| title_short | Patient iPSC-Derived Neurons for Disease Modeling of Frontotemporal Dementia with Mutation in CHMP2B |
| title_sort | patient ipsc derived neurons for disease modeling of frontotemporal dementia with mutation in chmp2b |
| topic | frontotemporal dementia linked to chromosome 3 (FTD3) CHMP2B iPSC-derived neuron disease modeling endosome mitochondria iron homeostasis oxidative stress neurodegeneration |
| url | http://www.sciencedirect.com/science/article/pii/S2213671117300279 |
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