Department of Medical Imaging, Anatomie, Radboud University Medical Center, Geert Grooteplein 10, Nijmegen, 6525 GA, the Netherlands; Department of Human Genetics, Radboudumc, Donders Institute for Brain, Cognition, and Behaviour, Nijmegen, 6500 HB, the Netherlands.
Department of Human Genetics, Radboudumc, Donders Institute for Brain, Cognition, and Behaviour, Nijmegen, 6500 HB, the Netherlands; Centre for Molecular and Biomolecular Informatics, Radboudumc, Nijmegen, the Netherlands.
Stem Cell Reports. 2021 Sep 14;16(9):2197-2212. doi: 10.1016/j.stemcr.2021.07.002. Epub 2021 Jul 29.
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is often caused by an adenine to guanine variant at m.3243 (m.3243A>G) of the MT-TL1 gene. To understand how this pathogenic variant 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 pathogenic variant. We combined micro-electrode array (MEA) measurements with RNA sequencing (MEA-seq) and found reduced 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 phase II drug sonlicromanol can improve neuronal network activity when treatment is initiated early in development. This was intricately linked with changes in the neuronal transcriptome. Overall, we provide insight in transcriptomic changes in iPSC-derived neurons with high m.3243A>G heteroplasmy, and show the pathology is partially reversible by sonlicromanol.
线粒体脑肌病、乳酸酸中毒和卒中样发作（MELAS）通常是由 MT-TL1 基因 m.3243（m.3243A>G）处的腺嘌呤到鸟嘌呤变异引起的。为了了解这种致病变异如何影响神经系统，我们从携带 m.3243A>G 致病变异的 MELAS 患者中分化出具有正常（低异质性）和受损（高异质性）线粒体功能的兴奋性神经元。我们将微电极阵列（MEA）测量与 RNA 测序（MEA-seq）相结合，发现与线粒体呼吸和突触前功能相关的基因表达降低，以及共培养的星形胶质细胞中的非细胞自主过程。最后，我们表明，临床二期药物 sonlicromanol 可以在早期发育时通过改变神经元转录组来改善神经元网络活动。这与神经元转录组的变化密切相关。总的来说，我们提供了高 m.3243A>G 异质性的 iPSC 衍生神经元中转录组变化的见解，并表明 sonlicromanol 可部分逆转病变。
