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

Yu Zhang, Benjamin Schmid, Nanett K Nikolaisen, Mikkel A Rasmussen, Blanca I Aldana, Mikkel Agger, Kirstine Calloe, Tina C Stummann, Hjalte M Larsen, Troels Nielsen, Jinrong Huang, Fengping Xu, Xin Liu, Lars Bolund, Morten Meyer, Lasse K Bak, Helle S Waagepetersen, Yonglun Luo, Jørgen E Nielsen, FReJA ConsortiumBjørn Holst, Christian Clausen, Poul Hyttel, Kristine K Freude

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

123 Downloads (Pure)

Resumé

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
Udgave nummer3
Sider (fra-til)648-658
ISSN2213-6711
DOI
StatusUdgivet - 2017

Fingeraftryk

Multivesicular Bodies
Stem cells
Neurons
Mutation
Proteins
Clustered Regularly Interspaced Short Palindromic Repeats
Iron
Endosomal Sorting Complexes Required for Transport
Neurodegenerative diseases
Mitochondria
Pathology
Chromosomes
Neurodegenerative Diseases
Respiration
Homeostasis
Oxygen
Degradation
Substrates
Pharmaceutical Preparations
In Vitro Techniques

Citer dette

Zhang, Y., Schmid, B., Nikolaisen, N. K., Rasmussen, M. A., Aldana, B. I., Agger, M., ... Freude, K. K. (2017). Patient iPSC-Derived Neurons for Disease Modeling of Frontotemporal Dementia with Mutation in CHMP2B. Stem Cell Reports, 8(3), 648-658. https://doi.org/10.1016/j.stemcr.2017.01.012
Zhang, Yu ; Schmid, Benjamin ; Nikolaisen, Nanett K ; Rasmussen, Mikkel A ; Aldana, Blanca I ; Agger, Mikkel ; Calloe, Kirstine ; Stummann, Tina C ; Larsen, Hjalte M ; Nielsen, Troels ; Huang, Jinrong ; Xu, Fengping ; Liu, Xin ; Bolund, Lars ; Meyer, Morten ; Bak, Lasse K ; Waagepetersen, Helle S ; Luo, Yonglun ; Nielsen, Jørgen E ; FReJA Consortium ; Holst, Bjørn ; Clausen, Christian ; Hyttel, Poul ; Freude, Kristine K. / Patient iPSC-Derived Neurons for Disease Modeling of Frontotemporal Dementia with Mutation in CHMP2B. I: Stem Cell Reports. 2017 ; Bind 8, Nr. 3. s. 648-658.
@article{adac019ee90b45b2ae28a6d5bb098611,
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.",
keywords = "Journal Article",
author = "Yu Zhang and Benjamin Schmid and Nikolaisen, {Nanett K} and Rasmussen, {Mikkel A} and Aldana, {Blanca I} and Mikkel Agger and Kirstine Calloe and Stummann, {Tina C} and Larsen, {Hjalte M} and Troels Nielsen and Jinrong Huang and Fengping Xu and Xin Liu and Lars Bolund and Morten Meyer and Bak, {Lasse K} and Waagepetersen, {Helle S} and Yonglun Luo and Nielsen, {J{\o}rgen E} and {FReJA Consortium} and Bj{\o}rn Holst and Christian Clausen and Poul Hyttel and Freude, {Kristine K}",
note = "Copyright {\circledC} 2017 The Author(s). Published by Elsevier Inc. All rights reserved.",
year = "2017",
doi = "10.1016/j.stemcr.2017.01.012",
language = "English",
volume = "8",
pages = "648--658",
journal = "Stem Cell Reports",
issn = "2213-6711",
publisher = "Cell Press",
number = "3",

}

Zhang, Y, Schmid, B, Nikolaisen, NK, Rasmussen, MA, Aldana, BI, Agger, M, Calloe, K, Stummann, TC, Larsen, HM, Nielsen, T, Huang, J, Xu, F, Liu, X, Bolund, L, Meyer, M, Bak, LK, Waagepetersen, HS, Luo, Y, Nielsen, JE, FReJA Consortium, Holst, B, Clausen, C, Hyttel, P & Freude, KK 2017, 'Patient iPSC-Derived Neurons for Disease Modeling of Frontotemporal Dementia with Mutation in CHMP2B', Stem Cell Reports, bind 8, nr. 3, s. 648-658. https://doi.org/10.1016/j.stemcr.2017.01.012

Patient iPSC-Derived Neurons for Disease Modeling of Frontotemporal Dementia with Mutation in CHMP2B. / Zhang, Yu; Schmid, Benjamin; Nikolaisen, Nanett K; Rasmussen, Mikkel A; Aldana, Blanca I; Agger, Mikkel; Calloe, Kirstine; Stummann, Tina C; Larsen, Hjalte M; Nielsen, Troels; Huang, Jinrong; Xu, Fengping; Liu, Xin; Bolund, Lars; Meyer, Morten; Bak, Lasse K; Waagepetersen, Helle S; Luo, Yonglun; Nielsen, Jørgen E; FReJA Consortium; Holst, Bjørn; Clausen, Christian; Hyttel, Poul; Freude, Kristine K.

I: Stem Cell Reports, Bind 8, Nr. 3, 2017, s. 648-658.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Patient iPSC-Derived Neurons for Disease Modeling of Frontotemporal Dementia with Mutation in CHMP2B

AU - Zhang, Yu

AU - Schmid, Benjamin

AU - Nikolaisen, Nanett K

AU - Rasmussen, Mikkel A

AU - Aldana, Blanca I

AU - Agger, Mikkel

AU - Calloe, Kirstine

AU - Stummann, Tina C

AU - Larsen, Hjalte M

AU - Nielsen, Troels

AU - Huang, Jinrong

AU - Xu, Fengping

AU - Liu, Xin

AU - Bolund, Lars

AU - Meyer, Morten

AU - Bak, Lasse K

AU - Waagepetersen, Helle S

AU - Luo, Yonglun

AU - Nielsen, Jørgen E

AU - FReJA Consortium

AU - Holst, Bjørn

AU - Clausen, Christian

AU - Hyttel, Poul

AU - Freude, Kristine K

N1 - Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1016/j.stemcr.2017.01.012

DO - 10.1016/j.stemcr.2017.01.012

M3 - Journal article

C2 - 28216144

VL - 8

SP - 648

EP - 658

JO - Stem Cell Reports

JF - Stem Cell Reports

SN - 2213-6711

IS - 3

ER -