Details

Autor(en) / Beteiligte

• Harjuhaahto, Sandra
• Rasila, Tiina S.
• Molchanova, Svetlana M.
• Woldegebriel, Rosa
• Kvist, Jouni
• Konovalova, Svetlana
• Sainio, Markus T.
• Pennonen, Jana
• Torregrosa-Muñumer, Rubén
• Ibrahim, Hazem
• Otonkoski, Timo
• Taira, Tomi
• Ylikallio, Emil
• Tyynismaa, Henna

Titel

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

Ist Teil von

• Neurobiology of disease, 2020-07, Vol.141, p.104940-104940, Article 104940

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2020

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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. •Mitochondrial CHCHD2/CHCHD10 are involved in Parkinson's and motor neuron diseases•Human iPSC lacking CHCHD2 or CHCHD10 differentiate into functional motor neurons•CHCHD2 and CHCHD10 impact mitochondrial respiration in motor neurons•Knockout motor neurons show altered synaptic gene expression