Sonlicromanol improves neuronal network dysfunction and transcriptome changes linked to m.3243A > G heteroplasmy in iPSC-derived neurons

Klein Gunnewiek, T. M.; Verboven, A. H. A.; Hogeweg, M.; Schoenmaker, C.; Renkema, H.; Beyrath, J.; Smeitink, J.; De Vries, B. B. A.; Kozicz, T.; 't Hoen, P. A. C.; Nadif Kasri, N. M.

doi:10.1101/2020.08.11.246140

bioRxiv · 10.1101/2020.08.11.246140

Sonlicromanol improves neuronal network dysfunction and transcriptome changes linked to m.3243A > G heteroplasmy in iPSC-derived neurons

Klein Gunnewiek, T. M.·Verboven, A. H. A.·Hogeweg, M.·Schoenmaker, C.·Renkema, H.·Beyrath, J.·Smeitink, J.·De Vries, B. B. A.·Kozicz, T.·'t Hoen, P. A. C.·Nadif Kasri, N. M.

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Abstract

Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) is often caused by an adenine to guanine mutation at m.3243 (m.3243A>G) of the MT-TL1 gene (tRNAleu(UUR)). To understand how this mutation affects the nervous system, we differentiated human induced-pluripotent stem cells (iPSCs) into excitatory neurons with normal (low heteroplasmy) and impaired (high heteroplasmy) mitochondrial function from MELAS patients with the m.3243A>G mutation. We combined micro-electrode array (MEA) measurements with RNA sequencing (MEA-seq) and found that the m.3243A>G mutation affects expression of genes involved in mitochondrial respiration- and presynaptic function, as well as non-cell autonomous processes in co-cultured astrocytes. Finally, we show that the clinical II stage drug sonlicromanol (KH176) improved neuronal network activity in a patient-specific manner when treatment is initiated early in development. This was intricately linked with changes in the neural transcriptome. Overall, MEA-seq is a powerful approach to identify mechanisms underlying the m.3243A>G mutation and to study the effect of pharmacological interventions in iPSC-derived neurons. Highlights- High m.3243A>G heteroplasmy leads to lower neuronal network activity and synchronicity - High heteroplasmy affects expression of genes involved in mitochondrial ATP production and the synaptic function / the presynaptic vesicle cycle - High neuronal heteroplasmy non cell autonomously affects gene expression in healthy co-cultured astrocytes - Sonlicromanol partially rescues neuronal network activity and transcriptome changes induced by high heteroplasmy eTOC BlurbUsing human inducible pluripotent stem cell-derived neurons with high levels of m.3243A>G heteroplasmy, Klein Gunnewiek et al. show transcriptome changes underlying the functional neuronal network phenotype, and how sonlicromanol can partially improve both this neuronal network phenotype, and the transcriptome changes, in a patient-specific manner.

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Klein Gunnewiek, T. M., Verboven, A. H. A., Hogeweg, M., Schoenmaker, C., Renkema, H., Beyrath, J., Smeitink, J., De Vries, B. B. A., Kozicz, T., 't Hoen, P. A. C., Nadif Kasri, N. M.. 2020-08-12. Sonlicromanol improves neuronal network dysfunction and transcriptome changes linked to m.3243A > G heteroplasmy in iPSC-derived neurons. https://doi.org/10.1101/2020.08.11.246140

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