ALS and Parkinson's disease genes CHCHD10 and CHCHD2 modify synaptic transcriptomes in human iPSC-derived motor neurons

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http://hdl.handle.net/10138/317778

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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: University of Helsinki, Research Programs Unit
University of Helsinki, STEMM - Stem Cells and Metabolism Research Program
University of Helsinki, Molecular and Integrative Biosciences Research Programme
University of Helsinki, STEMM - Stem Cells and Metabolism Research Program
University of Helsinki, STEMM - Stem Cells and Metabolism Research Program
University of Helsinki, Centre of Excellence in Stem Cell Metabolism
University of Helsinki, Centre of Excellence in Stem Cell Metabolism
University of Helsinki, STEMM - Stem Cells and Metabolism Research Program
University of Helsinki, STEMM - Stem Cells and Metabolism Research Program
University of Helsinki, Centre of Excellence in Stem Cell Metabolism
University of Helsinki, Helsinki One Health (HOH)
University of Helsinki, Veterinary Physiology
University of Helsinki, STEMM - Stem Cells and Metabolism Research Program
University of Helsinki, STEMM - Stem Cells and Metabolism Research Program
Date: 2020-07
Language: eng
Number of pages: 14
Belongs to series: Neurobiology of Disease
ISSN: 0969-9961
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
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