Patient iPSC-Derived Neurons for Disease Modeling of Frontotemporal Dementia with Mutation in CHMP2B
| Autor: | Zhang, Yu, Schmid, Benjamin, Qas Younan, Nanett Kvist, Rasmussen, Mikkel A., Garcia, Blanca Irene Aldana, Agger, Mikkel, Callø, Kirstine, Stummann, Tina C., Larsen, Hjalte M., Nielsen, Troels T., Huang, Jinrong, Xu, Fengping, Liu, Xin, Bolund, Lars, Meyer, Morten, Bak, Lasse Kristoffer, Waagepetersen, Helle S., Luo, Yonglun, Nielsen, Jørgen Erik, Consortium, The FReJA, Holst, Bjørn, Clausen, Christian, Hyttel, Poul, Freude, Kristine |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Mitochondrion Biochemistry 0302 clinical medicine disease modeling oxidative stress Induced pluripotent stem cell lcsh:QH301-705.5 Neurons Genetics lcsh:R5-920 Neurodegeneration CHMP2B neurodegeneration Cell Differentiation Cellular Reprogramming 3. Good health Cell biology mitochondria Frontotemporal Dementia lcsh:Medicine (General) Frontotemporal dementia Endosome Iron Induced Pluripotent Stem Cells Endosomes Biology Article ESCRT 03 medical and health sciences medicine Journal Article Humans iPSC-derived neuron endosome Endosomal Sorting Complexes Required for Transport Gene Expression Profiling Cell Biology Charged multivesicular body protein 2B frontotemporal dementia linked to chromosome 3 (FTD3) Fibroblasts medicine.disease 030104 developmental biology lcsh:Biology (General) Mutation iron homeostasis Transcriptome Cristae formation 030217 neurology & neurosurgery Developmental Biology |
| Zdroj: | Zhang, Y, Schmid, B, Nikolaisen, N K, Rasmussen, M A, Aldana, B I, Agger, M, Calloe, K, Stummann, T C, Larsen, H M, Nielsen, T, Huang, J, Xu, F, Liu, X, Bolund, L, Meyer, M, Bak, L K, Waagepetersen, H S, Luo, Y, Nielsen, J E, FReJA Consortium, Holst, B, Clausen, C, Hyttel, P & Freude, K K 2017, ' Patient iPSC-Derived Neurons for Disease Modeling of Frontotemporal Dementia with Mutation in CHMP2B ', Stem Cell Reports, vol. 8, no. 3, pp. 648-658 . https://doi.org/10.1016/j.stemcr.2017.01.012 Stem Cell Reports, Vol 8, Iss 3, Pp 648-658 (2017) Zhang, Y, Schmid, B, Nikolaisen, N K, Rasmussen, M A, Aldana, B I, Agger, M, Calloe, 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, Holst, B, Clausen, C, Hyttel, P, Freude, K K & FReJA Consortium 2017, ' Patient iPSC-Derived Neurons for Disease Modeling of Frontotemporal Dementia with Mutation in CHMP2B ', Stem Cell Reports, vol. 8, no. 3 . https://doi.org/10.1016/j.stemcr.2017.01.012 Stem Cell Reports Zhang, Y, Schmid, B, Qas Younan, 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, Consortium, T FRA, 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, vol. 8, no. 3, pp. 648-658 . https://doi.org/10.1016/j.stemcr.2017.01.012 |
| ISSN: | 2213-6711 |
| DOI: | 10.1016/j.stemcr.2017.01.012 |
| Popis: | Summary 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. Graphical Abstract Highlights • FTD3 neurons show abnormalities in endosomes and mitochondria • Parkinson's and Alzheimer's disease core genes are altered in FTD3 neurons • Iron homeostasis is perturbed in FTD3 neurons • Impairments in FTD3 neurons are rescued in CRISPR/Cas9-edited isogenic controls In this article, Freude, Zhang, and colleagues describe a patient iPSC-derived neuronal model for FTD3. This cellular model shows endosome abnormalities previously reported in patients. Furthermore, it provides insights into the role of impaired mitochondria function and imbalanced iron homeostasis in FTD3 pathology. All observed phenotypes were rescued in CRISPR/Cas9-edited isogenic controls. |
| Databáze: | OpenAIRE |
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