Institut for Biomedicin

Lars Bolund

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

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

  • Yu Zhang
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  • Benjamin Schmid, Bioneer A/S, 2970 Hørsholm, Denmark.
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  • Nanett Kvist Nikolaisen
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  • Mikkel A Rasmussen, Bioneer A/S, 2970 Hørsholm, Denmark.
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  • Blanca I Aldana, Neurometabolism Research Unit, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark.
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  • Mikkel Agger, Stem Cell and Developmental Neurobiology Group, Department of Neurobiology Research, University of Southern Denmark, 5000 Odense C, Denmark.
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  • Kirstine Calloe, The Physiology Group, Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg C, Denmark.
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  • Tina C Stummann, Discovery Chemistry and DMPK, H. Lundbeck A/S, Ottiliavej 9, 2500, Valby, Denmark.
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  • Hjalte M Larsen, 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.
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  • Troels T Nielsen, Neurogenetics Clinic & Research Lab, Danish Dementia Research Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
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  • Jinrong Huang, BGI-Shenzhen, 518083 Shenzhen, China; China National GeneBank-Shenzhen, BGI-Shenzhen, 518083 Shenzhen, China.
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  • Fengping Xu, BGI-Shenzhen, 518083 Shenzhen, China; China National GeneBank-Shenzhen, BGI-Shenzhen, 518083 Shenzhen, China.
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  • Xin Liu, BGI-Shenzhen, 518083 Shenzhen, China; China National GeneBank-Shenzhen, BGI-Shenzhen, 518083 Shenzhen, China.
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  • Lars Bolund
  • Morten Meyer, Stem Cell and Developmental Neurobiology Group, Department of Neurobiology Research, University of Southern Denmark, 5000 Odense C, Denmark.
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  • Lasse K Bak, Neurometabolism Research Unit, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark.
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  • Helle S Waagepetersen, Neurometabolism Research Unit, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark.
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  • Yonglun Luo
  • Jørgen E Nielsen, Neurogenetics Clinic & Research Lab, Danish Dementia Research Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
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  • Bjørn Holst, Bioneer A/S, 2970 Hørsholm, Denmark.
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  • Christian Clausen, Bioneer A/S, 2970 Hørsholm, Denmark.
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  • Poul Hyttel, 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.
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  • Kristine K Freude, 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.
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  • FReJA Consortium

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.

OriginalsprogEngelsk
TidsskriftStem Cell Reports
Vol/bind8
Nummer3
ISSN2213-6711
DOI
StatusUdgivet - 2017

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