title: Patient iPSC-Derived Neurons for Disease Modeling of Frontotemporal Dementia with Mutation in CHMP2B.
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.
authors.affiliation: 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.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Bioneer A/S, 2970 Hørsholm, Denmark.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Schmid
authors.affiliation: 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.
authors.forename: Nanett K
authors.initials: NK
authors.lastname: Nikolaisen
authors.affiliation: Bioneer A/S, 2970 Hørsholm, Denmark.
authors.forename: Mikkel A
authors.initials: MA
authors.lastname: Rasmussen
authors.affiliation: Neurometabolism Research Unit, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark.
authors.forename: Blanca I
authors.initials: BI
authors.lastname: Aldana
authors.affiliation: Stem Cell and Developmental Neurobiology Group, Department of Neurobiology Research, University of Southern Denmark, 5000 Odense C, Denmark.
authors.forename: Mikkel
authors.initials: M
authors.lastname: Agger
authors.affiliation: The Physiology Group, Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg C, Denmark.
authors.forename: Kirstine
authors.initials: K
authors.lastname: Calloe
authors.affiliation: H. Lundbeck A/S, 2500 Valby, Denmark.
authors.forename: Tina C
authors.initials: TC
authors.lastname: Stummann
authors.affiliation: 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.
authors.forename: Hjalte M
authors.initials: HM
authors.lastname: Larsen
authors.affiliation: Neurogenetics Clinic & Research Lab, Danish Dementia Research Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
authors.forename: Troels T
authors.initials: TT
authors.lastname: Nielsen
authors.affiliation: BGI-Shenzhen, 518083 Shenzhen, China; China National GeneBank-Shenzhen, BGI-Shenzhen, 518083 Shenzhen, China.
authors.forename: Jinrong
authors.initials: J
authors.lastname: Huang
authors.affiliation: BGI-Shenzhen, 518083 Shenzhen, China; China National GeneBank-Shenzhen, BGI-Shenzhen, 518083 Shenzhen, China.
authors.forename: Fengping
authors.initials: F
authors.lastname: Xu
authors.affiliation: BGI-Shenzhen, 518083 Shenzhen, China; China National GeneBank-Shenzhen, BGI-Shenzhen, 518083 Shenzhen, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Danish Regenerative Engineering Alliance for Medicine (DREAM), Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Bolund
authors.affiliation: Stem Cell and Developmental Neurobiology Group, Department of Neurobiology Research, University of Southern Denmark, 5000 Odense C, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Meyer
authors.affiliation: Neurometabolism Research Unit, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark.
authors.forename: Lasse K
authors.initials: LK
authors.lastname: Bak
authors.affiliation: Neurometabolism Research Unit, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark.
authors.forename: Helle S
authors.initials: HS
authors.lastname: Waagepetersen
authors.affiliation: Danish Regenerative Engineering Alliance for Medicine (DREAM), Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark.
authors.forename: Yonglun
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Neurogenetics Clinic & Research Lab, Danish Dementia Research Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
authors.forename: Jørgen E
authors.initials: JE
authors.lastname: Nielsen
authors.affiliation: Bioneer A/S, 2970 Hørsholm, Denmark.
authors.forename: Bjørn
authors.initials: B
authors.lastname: Holst
authors.affiliation: Bioneer A/S, 2970 Hørsholm, Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Clausen
authors.affiliation: 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.
authors.forename: Poul
authors.initials: P
authors.lastname: Hyttel
authors.affiliation: 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.
authors.forename: Kristine K
authors.initials: KK
authors.lastname: Freude
mesh_terms: D002454:Cell Differentiation; D065150:Cellular Reprogramming; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics*; D011992:Endosomes / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D057180:Frontotemporal Dementia / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D007501:Iron / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics; D059467:Transcriptome
chemical_list: C503812:CHMP2B protein, human; D056827:Endosomal Sorting Complexes Required for Transport; D007501:Iron
keywords: CHMP2B; disease modeling; endosome; frontotemporal dementia linked to chromosome 3 (FTD3); iPSC-derived neuron; iron homeostasis; mitochondria; neurodegeneration; oxidative stress