ALS and Parkinson's disease genes CHCHD10 and CHCHD2 modify synaptic transcriptomes in human iPSC-derived motor neurons
Mitochondrial intermembrane space proteins CHCHD2 and CHCHD10 have roles in motor neuron diseases such as amyotrophic lateral sclerosis, spinal muscular atrophy and axonal neuropathy and in Parkinson's disease. They form a complex of unknown function. Here we address the importance of these two...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-07-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996120302151 |
| _version_ | 1831547766391701504 |
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| author | Sandra Harjuhaahto Tiina S. Rasila Svetlana M. Molchanova Rosa Woldegebriel Jouni Kvist Svetlana Konovalova Markus T. Sainio Jana Pennonen Rubén Torregrosa-Muñumer Hazem Ibrahim Timo Otonkoski Tomi Taira Emil Ylikallio Henna Tyynismaa |
| author_facet | Sandra Harjuhaahto Tiina S. Rasila Svetlana M. Molchanova Rosa Woldegebriel Jouni Kvist Svetlana Konovalova Markus T. Sainio Jana Pennonen Rubén Torregrosa-Muñumer Hazem Ibrahim Timo Otonkoski Tomi Taira Emil Ylikallio Henna Tyynismaa |
| author_sort | Sandra Harjuhaahto |
| collection | DOAJ |
| description | Mitochondrial intermembrane space proteins CHCHD2 and CHCHD10 have roles in motor neuron diseases such as amyotrophic lateral sclerosis, spinal muscular atrophy and axonal neuropathy and in Parkinson's disease. They form a complex of unknown function. Here we address the importance of these two proteins in human motor neurons. We show that gene edited human induced pluripotent stem cells (iPSC) lacking either CHCHD2 or CHCHD10 are viable and can be differentiated into functional motor neurons that fire spontaneous and evoked action potentials. Mitochondria in knockout iPSC and motor neurons sustain ultrastructure but show increased proton leakage and respiration, and reciprocal compensatory increases in CHCHD2 or CHCHD10. Knockout motor neurons have largely overlapping transcriptome profiles compared to isogenic control line, in particular for synaptic gene expression. Our results show that the absence of either CHCHD2 or CHCHD10 alters mitochondrial respiration in human motor neurons, inducing similar compensatory responses. Thus, pathogenic mechanisms may involve loss of synaptic function resulting from defective energy metabolism. |
| first_indexed | 2024-12-17T02:08:48Z |
| format | Article |
| id | doaj.art-7dd3bc2f74c846f5b352a344121de51b |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-17T02:08:48Z |
| publishDate | 2020-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-7dd3bc2f74c846f5b352a344121de51b2022-12-21T22:07:38ZengElsevierNeurobiology of Disease1095-953X2020-07-01141104940ALS and Parkinson's disease genes CHCHD10 and CHCHD2 modify synaptic transcriptomes in human iPSC-derived motor neuronsSandra Harjuhaahto0Tiina S. Rasila1Svetlana M. Molchanova2Rosa Woldegebriel3Jouni Kvist4Svetlana Konovalova5Markus T. Sainio6Jana Pennonen7Rubén Torregrosa-Muñumer8Hazem Ibrahim9Timo Otonkoski10Tomi Taira11Emil Ylikallio12Henna Tyynismaa13Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, FinlandStem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, FinlandStem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Molecular and Integrative Biosciences Research Program, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, FinlandStem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, FinlandStem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, FinlandStem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, FinlandStem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, FinlandStem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, FinlandStem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, FinlandStem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, FinlandStem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, FinlandFaculty of Veterinary Medicine, Department of Veterinary Biosciences for Electrophysiology, University of Helsinki, Helsinki, Finland; Neuroscience Center, Helsinki Institute of Life Science, University of Helsinki, Helsinki, FinlandStem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Clinical Neurosciences, Neurology, Helsinki University Hospital, Helsinki, FinlandStem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Neuroscience Center, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland; Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland; Corresponding author at: Biomedicum Helsinki, r.C525b, Haartmaninkatu 8, 00290 Helsinki, Finland.Mitochondrial intermembrane space proteins CHCHD2 and CHCHD10 have roles in motor neuron diseases such as amyotrophic lateral sclerosis, spinal muscular atrophy and axonal neuropathy and in Parkinson's disease. They form a complex of unknown function. Here we address the importance of these two proteins in human motor neurons. We show that gene edited human induced pluripotent stem cells (iPSC) lacking either CHCHD2 or CHCHD10 are viable and can be differentiated into functional motor neurons that fire spontaneous and evoked action potentials. Mitochondria in knockout iPSC and motor neurons sustain ultrastructure but show increased proton leakage and respiration, and reciprocal compensatory increases in CHCHD2 or CHCHD10. Knockout motor neurons have largely overlapping transcriptome profiles compared to isogenic control line, in particular for synaptic gene expression. Our results show that the absence of either CHCHD2 or CHCHD10 alters mitochondrial respiration in human motor neurons, inducing similar compensatory responses. Thus, pathogenic mechanisms may involve loss of synaptic function resulting from defective energy metabolism.http://www.sciencedirect.com/science/article/pii/S0969996120302151CHCHD2CHCHD10Induced pluripotent stem cellMotor neuron differentiationCMT2SMAJ |
| spellingShingle | Sandra Harjuhaahto Tiina S. Rasila Svetlana M. Molchanova Rosa Woldegebriel Jouni Kvist Svetlana Konovalova Markus T. Sainio Jana Pennonen Rubén Torregrosa-Muñumer Hazem Ibrahim Timo Otonkoski Tomi Taira Emil Ylikallio Henna Tyynismaa ALS and Parkinson's disease genes CHCHD10 and CHCHD2 modify synaptic transcriptomes in human iPSC-derived motor neurons Neurobiology of Disease CHCHD2 CHCHD10 Induced pluripotent stem cell Motor neuron differentiation CMT2 SMAJ |
| title | ALS and Parkinson's disease genes CHCHD10 and CHCHD2 modify synaptic transcriptomes in human iPSC-derived motor neurons |
| title_full | ALS and Parkinson's disease genes CHCHD10 and CHCHD2 modify synaptic transcriptomes in human iPSC-derived motor neurons |
| title_fullStr | ALS and Parkinson's disease genes CHCHD10 and CHCHD2 modify synaptic transcriptomes in human iPSC-derived motor neurons |
| title_full_unstemmed | ALS and Parkinson's disease genes CHCHD10 and CHCHD2 modify synaptic transcriptomes in human iPSC-derived motor neurons |
| title_short | ALS and Parkinson's disease genes CHCHD10 and CHCHD2 modify synaptic transcriptomes in human iPSC-derived motor neurons |
| title_sort | als and parkinson s disease genes chchd10 and chchd2 modify synaptic transcriptomes in human ipsc derived motor neurons |
| topic | CHCHD2 CHCHD10 Induced pluripotent stem cell Motor neuron differentiation CMT2 SMAJ |
| url | http://www.sciencedirect.com/science/article/pii/S0969996120302151 |
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