Institute of Human Genetics, University of Cologne, Kerpener Str. 34, 50931, Cologne, Germany.
Center for Molecular Medicine, Cologne, University of Cologne, 50931, Cologne, Germany.
Acta Neuropathol Commun. 2020 Dec 22;8(1):223. doi: 10.1186/s40478-020-01101-6.
Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by loss of lower motor neurons, which leads to proximal muscle weakness and atrophy. SMA is caused by reduced survival motor neuron (SMN) protein levels due to biallelic deletions or mutations in the SMN1 gene. When SMN levels fall under a certain threshold, a plethora of cellular pathways are disturbed, including RNA processing, protein synthesis, metabolic defects, and mitochondrial function. Dysfunctional mitochondria can harm cells by decreased ATP production and increased oxidative stress due to elevated cellular levels of reactive oxygen species (ROS). Since neurons mainly produce energy via mitochondrial oxidative phosphorylation, restoring metabolic/oxidative homeostasis might rescue SMA pathology. Here, we report, based on proteome analysis, that SMA motor neurons show disturbed energy homeostasis due to dysfunction of mitochondrial complex I. This results in a lower basal ATP concentration and higher ROS production that causes an increase of protein carbonylation and impaired protein synthesis in SMA motor neurons. Counteracting these cellular impairments with pyruvate reduces elevated ROS levels, increases ATP and SMN protein levels in SMA motor neurons. Furthermore, we found that pyruvate-mediated SMN protein synthesis is mTOR-dependent. Most importantly, we showed that ROS regulates protein synthesis at the translational initiation step, which is impaired in SMA. As many neuropathies share pathological phenotypes such as dysfunctional mitochondria, excessive ROS, and impaired protein synthesis, our findings suggest new molecular interactions among these pathways. Additionally, counteracting these impairments by reducing ROS and increasing ATP might be beneficial for motor neuron survival in SMA patients.
脊髓性肌萎缩症（SMA）是一种以运动神经元丢失为特征的神经肌肉疾病，导致近端肌肉无力和萎缩。SMA 是由于 SMN1 基因的双等位基因缺失或突变导致运动神经元存活（SMN）蛋白水平降低引起的。当 SMN 水平降至一定阈值以下时，大量细胞通路被扰乱，包括 RNA 处理、蛋白质合成、代谢缺陷和线粒体功能。功能失调的线粒体通过减少 ATP 产生和增加由于细胞内活性氧（ROS）水平升高而导致的氧化应激来损害细胞。由于神经元主要通过线粒体氧化磷酸化产生能量，因此恢复代谢/氧化平衡可能会挽救 SMA 病理。在这里，我们根据蛋白质组分析报告，SMA 运动神经元由于线粒体复合物 I 的功能障碍而表现出能量稳态失调。这导致基础 ATP 浓度降低和 ROS 产生增加，从而导致蛋白质羰基化增加和 SMA 运动神经元中蛋白质合成受损。用丙酮酸对抗这些细胞损伤可降低升高的 ROS 水平，增加 SMA 运动神经元中的 ATP 和 SMN 蛋白水平。此外，我们发现丙酮酸介导的 SMN 蛋白合成依赖于 mTOR。最重要的是，我们表明 ROS 在翻译起始步骤调节蛋白质合成，而在 SMA 中则受损。由于许多神经病变具有相似的病理表型，如功能失调的线粒体、过多的 ROS 和受损的蛋白质合成，我们的研究结果表明这些途径之间存在新的分子相互作用。此外，通过降低 ROS 和增加 ATP 来对抗这些损伤可能有益于 SMA 患者运动神经元的存活。
