Harjuhaahto , S , Rasila , T S , Molchanova , S M , Woldegebriel , R , Kvist , J , Konovalova , S , Sainio , M T , Pennonen , J , Torregrosa-Munumer , R , Ibrahim , H , Otonkoski , T , Taira , T , Ylikallio , E & Tyynismaa , H 2020 , ' ALS and Parkinson's disease genes CHCHD10 and CHCHD2 modify synaptic transcriptomes in human iPSC-derived motor neurons ' , Neurobiology of Disease , vol. 141 , 104940 . https://doi.org/10.1016/j.nbd.2020.104940
Title: | ALS and Parkinson's disease genes CHCHD10 and CHCHD2 modify synaptic transcriptomes in human iPSC-derived motor neurons |
Author: | Harjuhaahto, Sandra; Rasila, Tiina S.; Molchanova, Svetlana M.; Woldegebriel, Rosa; Kvist, Jouni; Konovalova, Svetlana; Sainio, Markus T.; Pennonen, Jana; Torregrosa-Munumer, Ruben; Ibrahim, Hazem; Otonkoski, Timo; Taira, Tomi; Ylikallio, Emil; Tyynismaa, Henna |
Contributor organization: | Research Programs Unit STEMM - Stem Cells and Metabolism Research Program Faculty of Medicine University of Helsinki Molecular and Integrative Biosciences Research Programme Faculty of Biological and Environmental Sciences Centre of Excellence in Stem Cell Metabolism Henna Tyynismaa / Principal Investigator Helsinki One Health (HOH) HUS Children and Adolescents Timo Pyry Juhani Otonkoski / Principal Investigator Synaptic Plasticity and Neuronal Synchronization Veterinary Biosciences Tomi Taira / Principal Investigator Neuroscience Center Clinicum HUS Neurocenter Department of Neurosciences Neurologian yksikkö Helsinki University Hospital Area Department of Medical and Clinical Genetics Staff Services Helsinki Institute of Life Science HiLIFE Basal ganglia circuits |
Date: | 2020-07 |
Language: | eng |
Number of pages: | 14 |
Belongs to series: | Neurobiology of Disease |
ISSN: | 0969-9961 |
DOI: | https://doi.org/10.1016/j.nbd.2020.104940 |
URI: | http://hdl.handle.net/10138/317778 |
Abstract: | 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. |
Subject: |
CHCHD2
CHCHD10 Induced pluripotent stem cell Motor neuron differentiation CMT2 SMAJ ALS Mitochondria CRISPR/Cas9 RNA sequencing AMYOTROPHIC-LATERAL-SCLEROSIS PLURIPOTENT STEM-CELLS ENERGY-METABOLISM MUTATIONS POTENTIATION RECEPTORS GLUTAMATE RELEASE DPP6 3112 Neurosciences 3124 Neurology and psychiatry |
Peer reviewed: | Yes |
Rights: | cc_by_nc_nd |
Usage restriction: | openAccess |
Self-archived version: | publishedVersion |
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