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ALS and Parkinson's disease genes CHCHD10 and CHCHD2 modify synaptic transcriptomes in human iPSC-derived motor neurons.
- Source :
-
Neurobiology of disease [Neurobiol Dis] 2020 Jul; Vol. 141, pp. 104940. Date of Electronic Publication: 2020 May 11. - Publication Year :
- 2020
-
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.<br />Competing Interests: Declaration of Competing Interest The authors declare no competing interests.<br /> (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Amyotrophic Lateral Sclerosis metabolism
Cell Differentiation
Humans
Induced Pluripotent Stem Cells metabolism
Membrane Potentials
Mitochondria metabolism
Parkinson Disease metabolism
Amyotrophic Lateral Sclerosis genetics
DNA-Binding Proteins metabolism
Mitochondrial Proteins metabolism
Motor Neurons metabolism
Parkinson Disease genetics
Synapses metabolism
Transcription Factors metabolism
Transcriptome
Subjects
Details
- Language :
- English
- ISSN :
- 1095-953X
- Volume :
- 141
- Database :
- MEDLINE
- Journal :
- Neurobiology of disease
- Publication Type :
- Academic Journal
- Accession number :
- 32437855
- Full Text :
- https://doi.org/10.1016/j.nbd.2020.104940