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

Authors :
Harjuhaahto S
Rasila TS
Molchanova SM
Woldegebriel R
Kvist J
Konovalova S
Sainio MT
Pennonen J
Torregrosa-Muñumer R
Ibrahim H
Otonkoski T
Taira T
Ylikallio E
Tyynismaa H
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.)

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