Patient iPSC-derived neurons for disease modeling of frontotemporal dementia with mutation in CHMP2B

Yu Zhang; Benjamin Schmid; Nanett Kvist Nikolaisen; Mikkel A. Rasmussen; Blanca Irene Aldana Garcia; Mikkel Agger; Kirstine Callø; Tina C. Stummann; Hjalte M.  Larsen; Troels T.  Nielsen; Jinrong  Huang; Fengping Xu; Xin Liu; Lars Bolund; Morten Meyer; Lasse Kristoffer Bak; Helle S. Waagepetersen; Yonglun Luo; Jørgen Erik Nielsen; The FReJA  Consortium; Bjørn Holst; Christian Clausen; Poul Hyttel; Kristine Freude

doi:10.1016/j.stemcr.2017.01.012

Patient iPSC-derived neurons for disease modeling of frontotemporal dementia with mutation in CHMP2B

Yu Zhang, Benjamin Schmid, Nanett Kvist Nikolaisen, Mikkel A. Rasmussen, Blanca Irene Aldana Garcia, Mikkel Agger, Kirstine Callø, Tina C. Stummann, Hjalte M. Larsen, Troels T. Nielsen, Jinrong Huang, Fengping Xu, Xin Liu, Lars Bolund, Morten Meyer, Lasse Kristoffer Bak, Helle S. Waagepetersen, Yonglun Luo, Jørgen Erik Nielsen, The FReJA ConsortiumBjørn Holst, Christian Clausen, Poul Hyttel, Kristine Freude

Institut for Klinisk Medicin

34 Citationer (Scopus)

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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.

Originalsprog	Engelsk
Tidsskrift	Stem Cell Reports
Vol/bind	8
Udgave nummer	3
Sider (fra-til)	648-658
ISSN	2213-6711
DOI	https://doi.org/10.1016/j.stemcr.2017.01.012
Status	Udgivet - 14 mar. 2017

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10.1016/j.stemcr.2017.01.012Licens: CC BY-NC-ND

Zhang et al., 2017 Patient iPSC-Derived Neurons for Disease Modeling of Frontotemporal Dementia with Mutation in CHMP2BForlagets udgivne version, 25 MBLicens: CC BY-NC-ND

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Zhang, Y., Schmid, B., Nikolaisen, N. K., Rasmussen, M. A., Garcia, B. I. A., Agger, M., Callø, K., Stummann, T. C., Larsen, H. M., Nielsen, T. T., Huang, J., Xu, F., Liu, X., Bolund, L., Meyer, M., Bak, L. K., Waagepetersen, H. S., Luo, Y., Nielsen, J. E., ... Freude, 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, Y, Schmid, B, Nikolaisen, NK, Rasmussen, MA, Garcia, BIA, Agger, M, Callø, K, Stummann, TC, Larsen, HM, Nielsen, TT, Huang, J, Xu, F, Liu, X, Bolund, L, Meyer, M, Bak, LK , Waagepetersen, HS, Luo, Y, Nielsen, JE, Consortium, TFRA, Holst, B, Clausen, C, Hyttel, P & Freude, K 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

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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.",

author = "Yu Zhang and Benjamin Schmid and Nikolaisen, {Nanett Kvist} and Rasmussen, {Mikkel A.} and Garcia, {Blanca Irene Aldana} and Mikkel Agger and Kirstine Call{\o} and Stummann, {Tina C.} and Larsen, {Hjalte M.} and Nielsen, {Troels T.} and Jinrong Huang and Fengping Xu and Xin Liu and Lars Bolund and Morten Meyer and Bak, {Lasse Kristoffer} and Waagepetersen, {Helle S.} and Yonglun Luo and Nielsen, {J{\o}rgen Erik} and Consortium, {The FReJA} and Bj{\o}rn Holst and Christian Clausen and Poul Hyttel and Kristine Freude",

year = "2017",

month = mar,

day = "14",

doi = "10.1016/j.stemcr.2017.01.012",

language = "English",

volume = "8",

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journal = "Stem Cell Reports",

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T1 - Patient iPSC-derived neurons for disease modeling of frontotemporal dementia with mutation in CHMP2B

AU - Zhang, Yu

AU - Schmid, Benjamin

AU - Nikolaisen, Nanett Kvist

AU - Rasmussen, Mikkel A.

AU - Garcia, Blanca Irene Aldana

AU - Agger, Mikkel

AU - Callø, Kirstine

AU - Stummann, Tina C.

AU - Larsen, Hjalte M.

AU - Nielsen, Troels T.

AU - Huang, Jinrong

AU - Xu, Fengping

AU - Liu, Xin

AU - Bolund, Lars

AU - Meyer, Morten

AU - Bak, Lasse Kristoffer

AU - Waagepetersen, Helle S.

AU - Luo, Yonglun

AU - Nielsen, Jørgen Erik

AU - Consortium, The FReJA

AU - Holst, Bjørn

AU - Clausen, Christian

AU - Hyttel, Poul

AU - Freude, Kristine

PY - 2017/3/14

Y1 - 2017/3/14

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.

U2 - 10.1016/j.stemcr.2017.01.012

DO - 10.1016/j.stemcr.2017.01.012

M3 - Journal article

C2 - 28216144

SN - 2213-6711

VL - 8

SP - 648

EP - 658

JO - Stem Cell Reports

JF - Stem Cell Reports

IS - 3

ER -

Patient iPSC-derived neurons for disease modeling of frontotemporal dementia with mutation in CHMP2B

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